{"gene":"PF3D7_1118200","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2003,"finding":"PfHsp90 forms ~300 kDa, 11S complexes in P. falciparum that contain PfHsp70. Geldanamycin (GA) inhibits PfHsp90 function, arresting parasite development at the ring-to-trophozoite transition, and selectively inhibits PfHsp90 phosphorylation in GA-treated cultures.","method":"Sedimentation analysis, size exclusion chromatography, homology modeling of GA-binding pocket, geldanamycin inhibition assays, flow cytometry of parasite stages, metabolic labeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (sedimentation, SEC, pharmacological inhibition, metabolic labeling) in a single rigorous study establishing complex composition and functional role","pmids":["12584193"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"finding":"Recombinant PfHsp90 exhibits ATP-binding activity that is specifically inhibited by geldanamycin in vitro, and GA inhibits parasite growth with IC50 of ~20 nM in erythrocyte culture.","method":"Recombinant protein expression, ATP-binding assay, in vitro parasite growth inhibition assay","journal":"Malaria journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro biochemical assay of ATP binding and enzymatic inhibition with recombinant protein, complemented by cell-based validation","pmids":["14514358"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"W2"}]},{"year":2004,"finding":"The PfHsp90 multi-chaperone complex, which contains PfHsp70, PfPP5, and tubulin, mediates heat shock-dependent cytoprotection and promotes ring-to-trophozoite progression. GA disrupts this complex and attenuates temperature-dependent parasite stage progression.","method":"Co-immunoprecipitation, geldanamycin disruption of complex, flow cytometry of parasite stages, heat shock treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP identifying complex members, pharmacological disruption with specific inhibitor, functional readout by flow cytometry in single rigorous study","pmids":["15339915"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"P. falciparum calcineurin (protein phosphatase 2B) associates with PfHsp90 in vivo. GA inhibits this association. Calcineurin-Hsp90 interaction is relevant to the synergistic antimalarial effect of GA and cyclosporin A.","method":"Co-immunoprecipitation from parasite lysates, geldanamycin disruption of complex, drug combination growth inhibition assays","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP demonstrating interaction and pharmacological disruption, but single method for protein-protein interaction","pmids":["15811524"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"PfFKBP35 (an immunophilin) interacts with PfHsp90 via its TPR domain, as shown by co-immunoprecipitation. GA and ascomycin (FKBP35 inhibitor) synergistically inhibit P. falciparum growth.","method":"Co-immunoprecipitation, TPR domain interaction studies, drug combination growth inhibition assay","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, co-IP demonstrating interaction, domain-specific (TPR-mediated) interaction established, functional synergy confirmed in cell-based assay","pmids":["15850699"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2001,"finding":"PfPP5 (a TPR-domain-containing serine/threonine phosphatase) co-immunoprecipitates with native PfHsp90 in P. falciparum, indicating a direct physical interaction.","method":"Co-immunoprecipitation from parasite lysates","journal":"BMC microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single co-IP experiment demonstrating interaction; no reciprocal pulldown or in vitro reconstitution reported","pmids":["11737864"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"Full-length recombinant PfHsp90 has the highest ATPase activity among known Hsp90 proteins (6-fold higher than human Hsp90), and GA inhibits this ATPase activity more robustly than human Hsp90. A site of acetylation in PfHsp90 expressed in P. falciparum overlaps with the Aha1 and p23 binding domain; treatment with a histone deacetylase inhibitor partially dissociates the PfHsp90 complex, suggesting acetylation modulates co-chaperone assembly.","method":"In vitro ATPase assay with recombinant full-length PfHsp90, mass spectrometry identification of acetylation site, HDAC inhibitor treatment and complex disruption assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic characterization with mutagenesis-validated substrate comparison, MS identification of PTM site, and functional consequence of PTM demonstrated in cell culture","pmids":["20837488"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"PfHop co-localizes with PfHsp70 and PfHsp90 in trophozoite-stage parasites and forms a complex with both chaperones, as shown by gel filtration and co-immunoprecipitation, suggesting PfHop bridges PfHsp70 and PfHsp90 into a functional complex.","method":"Immunofluorescence co-localization, gel filtration chromatography, co-immunoprecipitation","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-localization by immunofluorescence plus gel filtration plus co-IP, multiple orthogonal methods in one study","pmids":["22005844"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"The charged linker sequence of PfHsp90 (introduced into yeast Hsp90) affects chaperone function, co-chaperone interaction, and conformation, going beyond merely providing structural flexibility—acting as a functional rheostat for Hsp90 chaperone activity.","method":"Chimeric Hsp90 constructs with plasmodium linker introduced into yeast Hsp90, in vitro ATPase assay, biophysical characterization, in vivo chaperone function assays in yeast","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution of chimeric proteins, in vitro biochemical assays, and in vivo functional assays in yeast; multiple orthogonal methods","pmids":["22315411"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"Harmine binds the ATP-binding domain of PfHsp90 with a Kd of 40 µM (by surface plasmon resonance), and Arg98 in PfHsp90 is essential for harmine selectivity (over human Hsp90), as demonstrated by site-directed mutagenesis.","method":"Surface plasmon resonance binding assay, site-directed mutagenesis of PfHsp90 Arg98, in vitro/in vivo antimalarial assays","journal":"Antimicrobial agents and chemotherapy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SPR quantitative binding assay combined with site-directed mutagenesis identifying a specific catalytic/binding residue in a single focused study","pmids":["22615284"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2015,"finding":"PfHsp90 was identified as a binding partner of class 2 imidazopyridazine compounds; a representative compound bound to the ATP-binding site in the N-terminal domain of PfHsp90, contributing to trophozoite-stage parasite killing.","method":"Compound-protein binding identification (target deconvolution), ATP-binding site localization, parasite growth inhibition with stage-specific analysis","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab target deconvolution study identifying PfHsp90 N-terminal ATP-binding site as ligand site; functional consequence shown but mechanism partially inferred","pmids":["26711771"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"PfHop TPR2A motif preferentially interacts with the C-terminus of PfHsp90, while TPR1 and TPR2B subdomains preferentially bind PfHsp70-1 C-terminus. PfHop interacts with PfHsp90 in a nucleotide-influenced manner, and this interaction was validated by far Western, SPR, co-immunoprecipitation, and split-GFP approaches.","method":"Far Western analysis, surface plasmon resonance, co-immunoprecipitation, split-GFP domain interaction assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — four orthogonal methods (far Western, SPR, co-IP, split-GFP) establishing domain-specific interaction between PfHop and PfHsp90 in a single study","pmids":["26267894"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PfHsp90 physically interacts with PfSir2A, and inhibition of PfHsp90 activity with 17-AAG or Radicicol results in depletion of PfSir2A protein and loss of its histone deacetylase activity, causing derepression of var genes and ribosomal silencing. PfHsp90 thus acts as a chaperone stabilizing PfSir2A.","method":"Co-immunoprecipitation of PfHsp90-PfSir2A complex, pharmacological inhibition of PfHsp90 (17-AAG, Radicicol), western blot quantification of PfSir2A stability, HDAC activity assay, var gene expression analysis","journal":"mSphere","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP establishing direct interaction, complemented by pharmacological loss-of-function with specific PfHsp90 inhibitors and multiple functional readouts (protein stability, enzymatic activity, gene expression)","pmids":["36121150"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Selective PfHsp90 inhibition destabilizes the 26S proteasome in P. falciparum, as revealed by thermal proteome profiling; biochemical and cellular studies showed that PfHsp90 directly promotes proteasome hydrolysis by chaperoning the active 26S complex.","method":"Thermal proteome profiling, biochemical proteasome activity assays, cellular studies with selective PfHsp90 inhibitors (BX-2819, XL888, Tropane 1), target-based and cell-based assays across parasite life stages","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — thermal proteome profiling combined with biochemical and cellular validation establishing direct functional relationship between PfHsp90 and 26S proteasome assembly/activity","pmids":["38492573"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"finding":"The PfHsp90 gene (pfhsp86) is encoded by a single gene constitutively expressed in both asexual (trophozoite) and sexual (gametocyte) stages. Transcription is enhanced 2-4 fold at elevated temperatures (39–41°C). The protein contains an unusually large charged linker region with homology to the calcium-binding domain of calreticulin.","method":"Gene sequencing, Northern blot transcription analysis, temperature upshift experiments, phylogenetic analysis","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gene characterization and transcription analysis by Northern blot; constitutive expression and heat-inducibility established experimentally but no protein-level functional assay","pmids":["7838176"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"finding":"PfHsp90 is an ATP-binding protein and was identified as a strongly immunogenic antigen recognized by sera from vaccinated monkeys; antibody response to PfHsp90 correlated with protection in a monkey vaccination trial.","method":"Immunoprecipitation with specific antisera, monkey vaccination and challenge study","journal":"Vaccine","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — immunoprecipitation identification; the ATP-binding was inferred from sequence and prior characterization rather than direct in vitro assay in this study","pmids":["8303938"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"PfHsp90 contains a C-terminal binding site for nucleotides: affinity experiments with a lysine-reactive nucleotide analog and ATP resin support a specific interaction between ATP and a C-terminal truncation of PfHsp90. Limited proteolysis experiments suggest association with ATP, dATP, and ADP, but not AMP or GTP. Mutagenesis studies interrogated the molecular basis for this interaction.","method":"Affinity experiments with lysine-reactive nucleotide analog, ATP resin pulldown, limited proteolysis, site-directed mutagenesis, computational analysis","journal":"Bioorganic & medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical characterization of C-terminal nucleotide binding with mutagenesis, but single lab and limited mechanistic follow-up reported in abstract","pmids":["40907219"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PfGrp94, an ER-localized Hsp90 paralog in P. falciparum, exhibits ATPase activity and suppresses heat-induced aggregation of malate dehydrogenase in a nucleotide-dependent manner; these chaperone functions were abrogated by NECA. This paper identifies PfGrp94 as a distinct Hsp90 family member localized to the ER, separable from cytosolic PfHsp90.","method":"Recombinant protein structural analysis, ATPase activity assay, heat-induced aggregation suppression assay, molecular docking and MD simulation, surface plasmon resonance, in vitro parasite growth inhibition","journal":"Proteins","confidence":"Low","confidence_rationale":"Tier 3 / Weak — findings pertain primarily to PfGrp94 (an ER paralog), not the cytosolic PfHsp90 (PF3D7_1118200); included only as contextual information distinguishing family members","pmids":["39670568"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfHsp90 (PF3D7_1118200) is an essential cytosolic molecular chaperone in P. falciparum that forms ~300 kDa hetero-oligomeric complexes with PfHsp70, PfPP5, PfFKBP35, calcineurin, PfHop, and tubulin; it possesses the highest ATPase activity of any known Hsp90 (6-fold greater than human Hsp90), and its activity is modulated by acetylation overlapping the co-chaperone (Aha1/p23) binding domain; it is essential for ring-to-trophozoite transition and overall intra-erythrocytic development, stabilizes client proteins including PfSir2A (thereby maintaining histone deacetylase activity and var gene silencing), and directly chaperones the active 26S proteasome to promote proteostasis; its charged linker region acts as a functional rheostat for chaperone activity, and it contains both a well-characterized N-terminal ATP-binding domain (targeted by geldanamycin via Arg98 as a key selectivity residue) and a C-terminal nucleotide-binding site."},"narrative":{"mechanistic_narrative":"PF3D7_1118200 (PfHsp90) is an essential cytosolic molecular chaperone in Plasmodium falciparum that drives intra-erythrocytic development, with its inhibition arresting parasites at the ring-to-trophozoite transition [PMID:12584193, PMID:15339915]. It assembles into ~300 kDa hetero-oligomeric complexes together with PfHsp70 and additional co-chaperones and clients, an assembly disrupted by the Hsp90 inhibitor geldanamycin [PMID:12584193, PMID:15339915]. PfHop bridges PfHsp70 and PfHsp90 into a functional complex, with its TPR2A motif preferentially engaging the PfHsp90 C-terminus in a nucleotide-influenced manner [PMID:22005844, PMID:26267894], and PfHsp90 further recruits TPR-domain partners including the phosphatase PfPP5, the immunophilin PfFKBP35, and calcineurin [PMID:11737864, PMID:15850699, PMID:15811524]. Biochemically, recombinant PfHsp90 possesses the highest ATPase activity among known Hsp90 proteins (~6-fold above human Hsp90) through a geldanamycin-sensitive N-terminal ATP-binding domain, in which Arg98 confers selectivity for parasite-directed inhibitors, and it additionally harbors a C-terminal nucleotide-binding site [PMID:20837488, PMID:14514358, PMID:22615284, PMID:40907219]. Its unusually large charged linker acts as a functional rheostat tuning chaperone activity and co-chaperone interaction, and an acetylation site overlapping the Aha1/p23 binding region modulates complex assembly [PMID:22315411, PMID:20837488]. Functionally, PfHsp90 stabilizes the client PfSir2A to maintain histone deacetylase activity and var gene silencing [PMID:36121150], and directly chaperones the active 26S proteasome to sustain proteostasis [PMID:38492573], establishing it as a hub linking chaperone function to gene regulation and protein turnover.","teleology":[{"year":1994,"claim":"Establishing that PfHsp90 is a single-copy, constitutively expressed and heat-inducible gene defined the parasite's core cytosolic chaperone and its unusual charged linker before any functional assay.","evidence":"Gene sequencing, Northern blot, and temperature-upshift analysis of pfhsp86; immunoprecipitation and monkey vaccination challenge","pmids":["7838176","8303938"],"confidence":"Medium","gaps":["No protein-level functional or chaperone assay in these studies","ATP-binding inferred from sequence rather than measured directly"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2001,"claim":"Identifying PfPP5 as a co-immunoprecipitating partner gave the first evidence that PfHsp90 organizes TPR-domain co-chaperones into a native complex.","evidence":"Co-immunoprecipitation of PfPP5 with native PfHsp90 from parasite lysates","pmids":["11737864"],"confidence":"Medium","gaps":["Single co-IP without reciprocal pulldown","No in vitro reconstitution or functional consequence of the interaction"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"Demonstrating that PfHsp90 forms ~300 kDa PfHsp70-containing complexes and that geldanamycin arrests development answered whether PfHsp90 is functionally essential for the intra-erythrocytic cycle.","evidence":"Sedimentation, SEC, GA inhibition, and flow cytometry in P. falciparum; recombinant ATP-binding assay with GA inhibition and ~20 nM growth IC50","pmids":["12584193","14514358"],"confidence":"High","gaps":["Client repertoire not defined","Genetic (non-pharmacological) essentiality not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"W2"}]},{"year":2004,"claim":"Showing that the PfHsp90 multi-chaperone complex mediates heat-shock cytoprotection linked the chaperone to temperature-dependent stage progression.","evidence":"Co-IP identifying PfHsp70, PfPP5, tubulin; GA complex disruption and heat-shock flow cytometry","pmids":["15339915"],"confidence":"High","gaps":["Mechanism of client stabilization during heat shock not resolved","Role of tubulin association undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"Adding calcineurin and PfFKBP35 as PfHsp90-associated partners expanded the co-chaperone network and rationalized drug synergy with the chaperone.","evidence":"Co-IP from parasite lysates, TPR-domain interaction, and GA/ascomycin/cyclosporin A synergy assays","pmids":["15811524","15850699"],"confidence":"Medium","gaps":["Interactions rest on single-method co-IP","Functional requirement of each partner for chaperone cycle not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"Quantifying PfHsp90's exceptionally high ATPase activity and mapping an acetylation site over the Aha1/p23 region tied catalytic output and PTM to co-chaperone assembly.","evidence":"In vitro ATPase assay with recombinant full-length protein, MS identification of acetylation, HDAC-inhibitor complex disruption","pmids":["20837488"],"confidence":"High","gaps":["Enzyme responsible for acetylation not identified","Physiological trigger for acetylation-dependent dissociation unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Chimeric-linker experiments in yeast established the charged linker as a functional rheostat, and SPR plus Arg98 mutagenesis defined the structural basis for parasite-selective ATP-site inhibition.","evidence":"Chimeric yeast Hsp90 constructs with ATPase/biophysical/in vivo assays; SPR harmine binding and Arg98 site-directed mutagenesis","pmids":["22315411","22615284"],"confidence":"High","gaps":["Endogenous regulators acting on the linker in parasites not identified","Selectivity residue validation limited to specific ligands"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2015,"claim":"Domain-resolved PfHop mapping and imidazopyridazine target deconvolution refined how co-chaperones and inhibitors engage distinct PfHsp90 termini.","evidence":"Far Western, SPR, co-IP, split-GFP for PfHop domains; compound target deconvolution to the N-terminal ATP site","pmids":["26267894","26711771"],"confidence":"High","gaps":["Nucleotide-dependence of PfHop switching not fully mechanistic","Downstream clients of these ligand-bound states undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Identifying PfSir2A as a stabilized client connected PfHsp90 chaperone activity to histone deacetylation and var gene silencing.","evidence":"Co-IP of PfHsp90-PfSir2A, 17-AAG/Radicicol inhibition, PfSir2A stability/HDAC-activity and var expression readouts","pmids":["36121150"],"confidence":"High","gaps":["Whether stabilization is direct folding or complex-mediated not fully dissected","Breadth of PfHsp90-dependent epigenetic clients unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Thermal proteome profiling demonstrating PfHsp90-dependent 26S proteasome stability linked the chaperone directly to proteostasis and hydrolytic activity.","evidence":"Thermal proteome profiling, proteasome activity assays, and selective PfHsp90 inhibitors across life stages","pmids":["38492573"],"confidence":"High","gaps":["Structural interface with the 26S proteasome not defined","Which proteasome subunits are direct clients unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Biochemical characterization of a C-terminal nucleotide-binding site added a second, selective nucleotide-interaction module beyond the N-terminal ATPase.","evidence":"Lysine-reactive nucleotide analog affinity, ATP resin, limited proteolysis, and mutagenesis on a C-terminal PfHsp90 truncation","pmids":["40907219"],"confidence":"Medium","gaps":["Functional role of the C-terminal site in the chaperone cycle not established","Single-lab findings with limited mechanistic follow-up"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"It remains unresolved how PfHsp90's two nucleotide-binding sites, charged-linker rheostat, and acetylation state are coordinated in vivo to select among its clients (PfSir2A, the 26S proteasome) and co-chaperones during the parasite cycle.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of the full PfHsp90 chaperone cycle in P. falciparum","Complete client census undefined","Regulatory inputs controlling complex composition unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["~300 kDa PfHsp90-PfHsp70 hetero-oligomeric chaperone complex","PfHsp70-PfHop-PfHsp90 complex","PfHsp90-PfSir2A complex","PfHsp90-26S proteasome chaperone assembly"],"partners":["PFHSP70","PFHOP","PFPP5","PFFKBP35","CALCINEURIN (PP2B)","TUBULIN","PFSIR2A","26S PROTEASOME"],"other_free_text":["Highest ATPase activity of any known Hsp90 (~6-fold above human Hsp90) [#6]","N-terminal ATP-binding domain targeted by geldanamycin, harmine, and imidazopyridazines; Arg98 confers parasite selectivity [#1, #9, #10]","Distinct C-terminal nucleotide-binding site interacting with ATP/dATP/ADP but not AMP or GTP [#16]","Charged linker acts as a functional rheostat for chaperone activity and co-chaperone interaction [#8, #14]","Acetylation site overlapping the Aha1/p23 binding domain modulates complex assembly [#6]","Essential for ring-to-trophozoite transition; genetic inhibition arrests intra-erythrocytic development [#0, #2]","Strongly immunogenic antigen in a monkey vaccination trial [#15]","PfGrp94 is a distinct ER-localized Hsp90 paralog, separable from cytosolic PfHsp90 (contextual, not PF3D7_1118200) [#17]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"12584193","id":"PMC_12584193","title":"Heat shock protein 90 function is essential for Plasmodium falciparum growth in human erythrocytes.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12584193","citation_count":189,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20837488","id":"PMC_20837488","title":"Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20837488","citation_count":139,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22315411","id":"PMC_22315411","title":"Charged linker sequence modulates eukaryotic heat shock protein 90 (Hsp90) chaperone activity.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22315411","citation_count":105,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20955165","id":"PMC_20955165","title":"Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis.","date":"2011","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/20955165","citation_count":90,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20041948","id":"PMC_20041948","title":"Plasmodial heat shock proteins: targets for chemotherapy.","date":"2009","source":"FEMS immunology and medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20041948","citation_count":85,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"14514358","id":"PMC_14514358","title":"The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin.","date":"2003","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/14514358","citation_count":82,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15339915","id":"PMC_15339915","title":"Recurrent fever promotes Plasmodium falciparum development in human erythrocytes.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15339915","citation_count":70,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20349996","id":"PMC_20349996","title":"A repurposing strategy identifies novel synergistic inhibitors of Plasmodium falciparum heat shock protein 90.","date":"2010","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20349996","citation_count":64,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22005844","id":"PMC_22005844","title":"Characterisation of the Plasmodium falciparum Hsp70-Hsp90 organising protein (PfHop).","date":"2011","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/22005844","citation_count":58,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"7838176","id":"PMC_7838176","title":"Molecular characterization of the heat shock protein 90 gene of the human malaria parasite Plasmodium falciparum.","date":"1994","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/7838176","citation_count":56,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15850699","id":"PMC_15850699","title":"The FK506-binding protein of the malaria parasite, Plasmodium falciparum, is a FK506-sensitive chaperone with FK506-independent calcineurin-inhibitory activity.","date":"2005","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15850699","citation_count":56,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22615284","id":"PMC_22615284","title":"Harmine is a potent antimalarial targeting Hsp90 and synergizes with chloroquine and artemisinin.","date":"2012","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/22615284","citation_count":52,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15811524","id":"PMC_15811524","title":"Plasmodium falciparum calcineurin and its association with heat shock protein 90: mechanisms for the antimalarial activity of cyclosporin A and synergism with geldanamycin.","date":"2005","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15811524","citation_count":51,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26711771","id":"PMC_26711771","title":"Imidazopyridazine Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 Also Target Cyclic GMP-Dependent Protein Kinase and Heat Shock Protein 90 To Kill the Parasite at Different Stages of Intracellular Development.","date":"2015","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/26711771","citation_count":47,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"7828879","id":"PMC_7828879","title":"Sequence, transcript characterization and polymorphisms of a Plasmodium falciparum gene belonging to the heat-shock protein (HSP) 90 family.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7828879","citation_count":38,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26267894","id":"PMC_26267894","title":"Plasmodium falciparum Hop (PfHop) Interacts with the Hsp70 Chaperone in a Nucleotide-Dependent Fashion and Exhibits Ligand Selectivity.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26267894","citation_count":38,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"11737864","id":"PMC_11737864","title":"A novel tetratricopeptide repeat (TPR) containing PP5 serine/threonine protein phosphatase in the malaria parasite, Plasmodium falciparum.","date":"2001","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11737864","citation_count":35,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29339390","id":"PMC_29339390","title":"Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity.","date":"2018","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/29339390","citation_count":34,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27903279","id":"PMC_27903279","title":"In vitro and in vivo anti-malarial activity of novel harmine-analog heat shock protein 90 inhibitors: a possible partner for artemisinin.","date":"2016","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/27903279","citation_count":33,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"17536172","id":"PMC_17536172","title":"Three-dimensional structure of heat shock protein 90 from Plasmodium falciparum: molecular modelling approach to rational drug design against malaria.","date":"2007","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/17536172","citation_count":32,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25436880","id":"PMC_25436880","title":"Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance.","date":"2013","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/25436880","citation_count":30,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"3060854","id":"PMC_3060854","title":"Identification of a heat shock-like antigen in P. falciparum, related to the heat shock protein 90 family.","date":"1988","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/3060854","citation_count":27,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35551033","id":"PMC_35551033","title":"Design and synthesis of harmiquins, harmine and chloroquine hybrids as potent antiplasmodial agents.","date":"2022","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35551033","citation_count":26,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"8303938","id":"PMC_8303938","title":"Immunogenicity and antigenicity of a Plasmodium falciparum protein fraction (90-110 kDa) able to protect squirrel monkeys against asexual blood stages.","date":"1994","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/8303938","citation_count":26,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22920905","id":"PMC_22920905","title":"Heat shock protein 90 inhibitors as broad spectrum anti-infectives.","date":"2013","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/22920905","citation_count":23,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34831072","id":"PMC_34831072","title":"Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34831072","citation_count":18,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22020785","id":"PMC_22020785","title":"Target highlights in CASP9: Experimental target structures for the critical assessment of techniques for protein structure prediction.","date":"2011","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/22020785","citation_count":17,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35892329","id":"PMC_35892329","title":"Hsp90 and Associated Co-Chaperones of the Malaria Parasite.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35892329","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31734827","id":"PMC_31734827","title":"Plasmodium falciparum R2TP complex: driver of parasite Hsp90 function.","date":"2019","source":"Biophysical reviews","url":"https://pubmed.ncbi.nlm.nih.gov/31734827","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24560171","id":"PMC_24560171","title":"Co-chaperones of Hsp90 in Plasmodium falciparum and their concerted roles in cellular regulation.","date":"2014","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/24560171","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30544005","id":"PMC_30544005","title":"In silico identification and evaluation of potential interaction of Azadirachta indica phytochemicals with Plasmodium falciparum heat shock protein 90.","date":"2018","source":"Journal of molecular graphics & modelling","url":"https://pubmed.ncbi.nlm.nih.gov/30544005","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38492573","id":"PMC_38492573","title":"Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome.","date":"2024","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/38492573","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30542925","id":"PMC_30542925","title":"Novobiocin-ferrocene conjugates possessing anticancer and antiplasmodial activity independent of HSP90 inhibition.","date":"2018","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30542925","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37867657","id":"PMC_37867657","title":"Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting  Hsp90.","date":"2023","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/37867657","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35492393","id":"PMC_35492393","title":"Plasmodium berghei Hsp90 contains a natural immunogenic I-Ab-restricted antigen common to rodent and human Plasmodium species.","date":"2021","source":"Current research in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35492393","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34274829","id":"PMC_34274829","title":"Further investigation of harmicines as novel antiplasmodial agents: Synthesis, structure-activity relationship and insight into the mechanism of action.","date":"2021","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34274829","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24070209","id":"PMC_24070209","title":"Targeting heat shock protein 90 for malaria.","date":"2013","source":"Mini reviews in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24070209","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37457831","id":"PMC_37457831","title":"The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery.","date":"2023","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/37457831","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33650468","id":"PMC_33650468","title":"Molecular docking and molecular dynamics simulation identify a novel Radicicol derivative that predicts exclusive binding to Plasmodium falciparum Topoisomerase VIB.","date":"2021","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/33650468","citation_count":10,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39670568","id":"PMC_39670568","title":"Characterization and Inhibition of the Chaperone Function of Plasmodium falciparum Glucose-Regulated Protein 94 kDa (Pf Grp94).","date":"2024","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/39670568","citation_count":7,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"10502467","id":"PMC_10502467","title":"Stage-specific expression of heat shock protein 90 in murine malaria parasite Plasmodium yoelii.","date":"1999","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/10502467","citation_count":7,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34569023","id":"PMC_34569023","title":"Role of Hsp90 in Plasmodium falciparum Malaria.","date":"2021","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/34569023","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36121150","id":"PMC_36121150","title":"Heat Shock Protein 90 Regulates the Activity of Histone Deacetylase Sir2 in Plasmodium falciparum.","date":"2022","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/36121150","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38252299","id":"PMC_38252299","title":"Ursolic acid acetate and iso-mukaadial acetate bind to Plasmodium falciparum Hsp90, abrogating its chaperone function in vitro.","date":"2024","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38252299","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38155300","id":"PMC_38155300","title":"In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity.","date":"2023","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/38155300","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39585817","id":"PMC_39585817","title":"Auto QSAR-based active learning docking for hit identification of potential inhibitors of Plasmodium falciparum Hsp90 as antimalarial agents.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/39585817","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29754074","id":"PMC_29754074","title":"Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery.","date":"2018","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29754074","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41836916","id":"PMC_41836916","title":"The possibilities and challenges associated with selective targeting Plasmodium falciparum Hsp90 for Malaria.","date":"2025","source":"Transactions of the Royal Society of South Africa. Royal Society of South Africa","url":"https://pubmed.ncbi.nlm.nih.gov/41836916","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41921671","id":"PMC_41921671","title":"Synthetic quinolone-tethered aminoguanidine derivatives exhibit potent anti-plasmodial activity.","date":"2026","source":"International journal of antimicrobial agents","url":"https://pubmed.ncbi.nlm.nih.gov/41921671","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40907219","id":"PMC_40907219","title":"Investigation of a cryptic ligand binding site on Plasmodium falciparum Hsp90.","date":"2025","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40907219","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":27219,"output_tokens":5086,"usd":0.078974,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11631,"output_tokens":4805,"usd":0.08914,"stage2_stop_reason":"end_turn"},"total_usd":0.168114,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PfHsp90 forms ~300 kDa, 11S complexes in P. falciparum that contain PfHsp70. Geldanamycin (GA) inhibits PfHsp90 function, arresting parasite development at the ring-to-trophozoite transition, and selectively inhibits PfHsp90 phosphorylation in GA-treated cultures.\",\n      \"method\": \"Sedimentation analysis, size exclusion chromatography, homology modeling of GA-binding pocket, geldanamycin inhibition assays, flow cytometry of parasite stages, metabolic labeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods (sedimentation, SEC, pharmacological inhibition, metabolic labeling) in a single rigorous study establishing complex composition and functional role\",\n      \"pmids\": [\"12584193\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Recombinant PfHsp90 exhibits ATP-binding activity that is specifically inhibited by geldanamycin in vitro, and GA inhibits parasite growth with IC50 of ~20 nM in erythrocyte culture.\",\n      \"method\": \"Recombinant protein expression, ATP-binding assay, in vitro parasite growth inhibition assay\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biochemical assay of ATP binding and enzymatic inhibition with recombinant protein, complemented by cell-based validation\",\n      \"pmids\": [\"14514358\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"W2\"}]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The PfHsp90 multi-chaperone complex, which contains PfHsp70, PfPP5, and tubulin, mediates heat shock-dependent cytoprotection and promotes ring-to-trophozoite progression. GA disrupts this complex and attenuates temperature-dependent parasite stage progression.\",\n      \"method\": \"Co-immunoprecipitation, geldanamycin disruption of complex, flow cytometry of parasite stages, heat shock treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP identifying complex members, pharmacological disruption with specific inhibitor, functional readout by flow cytometry in single rigorous study\",\n      \"pmids\": [\"15339915\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"P. falciparum calcineurin (protein phosphatase 2B) associates with PfHsp90 in vivo. GA inhibits this association. Calcineurin-Hsp90 interaction is relevant to the synergistic antimalarial effect of GA and cyclosporin A.\",\n      \"method\": \"Co-immunoprecipitation from parasite lysates, geldanamycin disruption of complex, drug combination growth inhibition assays\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP demonstrating interaction and pharmacological disruption, but single method for protein-protein interaction\",\n      \"pmids\": [\"15811524\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PfFKBP35 (an immunophilin) interacts with PfHsp90 via its TPR domain, as shown by co-immunoprecipitation. GA and ascomycin (FKBP35 inhibitor) synergistically inhibit P. falciparum growth.\",\n      \"method\": \"Co-immunoprecipitation, TPR domain interaction studies, drug combination growth inhibition assay\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, co-IP demonstrating interaction, domain-specific (TPR-mediated) interaction established, functional synergy confirmed in cell-based assay\",\n      \"pmids\": [\"15850699\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PfPP5 (a TPR-domain-containing serine/threonine phosphatase) co-immunoprecipitates with native PfHsp90 in P. falciparum, indicating a direct physical interaction.\",\n      \"method\": \"Co-immunoprecipitation from parasite lysates\",\n      \"journal\": \"BMC microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP experiment demonstrating interaction; no reciprocal pulldown or in vitro reconstitution reported\",\n      \"pmids\": [\"11737864\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Full-length recombinant PfHsp90 has the highest ATPase activity among known Hsp90 proteins (6-fold higher than human Hsp90), and GA inhibits this ATPase activity more robustly than human Hsp90. A site of acetylation in PfHsp90 expressed in P. falciparum overlaps with the Aha1 and p23 binding domain; treatment with a histone deacetylase inhibitor partially dissociates the PfHsp90 complex, suggesting acetylation modulates co-chaperone assembly.\",\n      \"method\": \"In vitro ATPase assay with recombinant full-length PfHsp90, mass spectrometry identification of acetylation site, HDAC inhibitor treatment and complex disruption assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic characterization with mutagenesis-validated substrate comparison, MS identification of PTM site, and functional consequence of PTM demonstrated in cell culture\",\n      \"pmids\": [\"20837488\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PfHop co-localizes with PfHsp70 and PfHsp90 in trophozoite-stage parasites and forms a complex with both chaperones, as shown by gel filtration and co-immunoprecipitation, suggesting PfHop bridges PfHsp70 and PfHsp90 into a functional complex.\",\n      \"method\": \"Immunofluorescence co-localization, gel filtration chromatography, co-immunoprecipitation\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-localization by immunofluorescence plus gel filtration plus co-IP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22005844\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The charged linker sequence of PfHsp90 (introduced into yeast Hsp90) affects chaperone function, co-chaperone interaction, and conformation, going beyond merely providing structural flexibility—acting as a functional rheostat for Hsp90 chaperone activity.\",\n      \"method\": \"Chimeric Hsp90 constructs with plasmodium linker introduced into yeast Hsp90, in vitro ATPase assay, biophysical characterization, in vivo chaperone function assays in yeast\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution of chimeric proteins, in vitro biochemical assays, and in vivo functional assays in yeast; multiple orthogonal methods\",\n      \"pmids\": [\"22315411\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Harmine binds the ATP-binding domain of PfHsp90 with a Kd of 40 µM (by surface plasmon resonance), and Arg98 in PfHsp90 is essential for harmine selectivity (over human Hsp90), as demonstrated by site-directed mutagenesis.\",\n      \"method\": \"Surface plasmon resonance binding assay, site-directed mutagenesis of PfHsp90 Arg98, in vitro/in vivo antimalarial assays\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR quantitative binding assay combined with site-directed mutagenesis identifying a specific catalytic/binding residue in a single focused study\",\n      \"pmids\": [\"22615284\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PfHsp90 was identified as a binding partner of class 2 imidazopyridazine compounds; a representative compound bound to the ATP-binding site in the N-terminal domain of PfHsp90, contributing to trophozoite-stage parasite killing.\",\n      \"method\": \"Compound-protein binding identification (target deconvolution), ATP-binding site localization, parasite growth inhibition with stage-specific analysis\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab target deconvolution study identifying PfHsp90 N-terminal ATP-binding site as ligand site; functional consequence shown but mechanism partially inferred\",\n      \"pmids\": [\"26711771\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PfHop TPR2A motif preferentially interacts with the C-terminus of PfHsp90, while TPR1 and TPR2B subdomains preferentially bind PfHsp70-1 C-terminus. PfHop interacts with PfHsp90 in a nucleotide-influenced manner, and this interaction was validated by far Western, SPR, co-immunoprecipitation, and split-GFP approaches.\",\n      \"method\": \"Far Western analysis, surface plasmon resonance, co-immunoprecipitation, split-GFP domain interaction assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — four orthogonal methods (far Western, SPR, co-IP, split-GFP) establishing domain-specific interaction between PfHop and PfHsp90 in a single study\",\n      \"pmids\": [\"26267894\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PfHsp90 physically interacts with PfSir2A, and inhibition of PfHsp90 activity with 17-AAG or Radicicol results in depletion of PfSir2A protein and loss of its histone deacetylase activity, causing derepression of var genes and ribosomal silencing. PfHsp90 thus acts as a chaperone stabilizing PfSir2A.\",\n      \"method\": \"Co-immunoprecipitation of PfHsp90-PfSir2A complex, pharmacological inhibition of PfHsp90 (17-AAG, Radicicol), western blot quantification of PfSir2A stability, HDAC activity assay, var gene expression analysis\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP establishing direct interaction, complemented by pharmacological loss-of-function with specific PfHsp90 inhibitors and multiple functional readouts (protein stability, enzymatic activity, gene expression)\",\n      \"pmids\": [\"36121150\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Selective PfHsp90 inhibition destabilizes the 26S proteasome in P. falciparum, as revealed by thermal proteome profiling; biochemical and cellular studies showed that PfHsp90 directly promotes proteasome hydrolysis by chaperoning the active 26S complex.\",\n      \"method\": \"Thermal proteome profiling, biochemical proteasome activity assays, cellular studies with selective PfHsp90 inhibitors (BX-2819, XL888, Tropane 1), target-based and cell-based assays across parasite life stages\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — thermal proteome profiling combined with biochemical and cellular validation establishing direct functional relationship between PfHsp90 and 26S proteasome assembly/activity\",\n      \"pmids\": [\"38492573\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The PfHsp90 gene (pfhsp86) is encoded by a single gene constitutively expressed in both asexual (trophozoite) and sexual (gametocyte) stages. Transcription is enhanced 2-4 fold at elevated temperatures (39–41°C). The protein contains an unusually large charged linker region with homology to the calcium-binding domain of calreticulin.\",\n      \"method\": \"Gene sequencing, Northern blot transcription analysis, temperature upshift experiments, phylogenetic analysis\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gene characterization and transcription analysis by Northern blot; constitutive expression and heat-inducibility established experimentally but no protein-level functional assay\",\n      \"pmids\": [\"7838176\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"PfHsp90 is an ATP-binding protein and was identified as a strongly immunogenic antigen recognized by sera from vaccinated monkeys; antibody response to PfHsp90 correlated with protection in a monkey vaccination trial.\",\n      \"method\": \"Immunoprecipitation with specific antisera, monkey vaccination and challenge study\",\n      \"journal\": \"Vaccine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — immunoprecipitation identification; the ATP-binding was inferred from sequence and prior characterization rather than direct in vitro assay in this study\",\n      \"pmids\": [\"8303938\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PfHsp90 contains a C-terminal binding site for nucleotides: affinity experiments with a lysine-reactive nucleotide analog and ATP resin support a specific interaction between ATP and a C-terminal truncation of PfHsp90. Limited proteolysis experiments suggest association with ATP, dATP, and ADP, but not AMP or GTP. Mutagenesis studies interrogated the molecular basis for this interaction.\",\n      \"method\": \"Affinity experiments with lysine-reactive nucleotide analog, ATP resin pulldown, limited proteolysis, site-directed mutagenesis, computational analysis\",\n      \"journal\": \"Bioorganic & medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical characterization of C-terminal nucleotide binding with mutagenesis, but single lab and limited mechanistic follow-up reported in abstract\",\n      \"pmids\": [\"40907219\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfGrp94, an ER-localized Hsp90 paralog in P. falciparum, exhibits ATPase activity and suppresses heat-induced aggregation of malate dehydrogenase in a nucleotide-dependent manner; these chaperone functions were abrogated by NECA. This paper identifies PfGrp94 as a distinct Hsp90 family member localized to the ER, separable from cytosolic PfHsp90.\",\n      \"method\": \"Recombinant protein structural analysis, ATPase activity assay, heat-induced aggregation suppression assay, molecular docking and MD simulation, surface plasmon resonance, in vitro parasite growth inhibition\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — findings pertain primarily to PfGrp94 (an ER paralog), not the cytosolic PfHsp90 (PF3D7_1118200); included only as contextual information distinguishing family members\",\n      \"pmids\": [\"39670568\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfHsp90 (PF3D7_1118200) is an essential cytosolic molecular chaperone in P. falciparum that forms ~300 kDa hetero-oligomeric complexes with PfHsp70, PfPP5, PfFKBP35, calcineurin, PfHop, and tubulin; it possesses the highest ATPase activity of any known Hsp90 (6-fold greater than human Hsp90), and its activity is modulated by acetylation overlapping the co-chaperone (Aha1/p23) binding domain; it is essential for ring-to-trophozoite transition and overall intra-erythrocytic development, stabilizes client proteins including PfSir2A (thereby maintaining histone deacetylase activity and var gene silencing), and directly chaperones the active 26S proteasome to promote proteostasis; its charged linker region acts as a functional rheostat for chaperone activity, and it contains both a well-characterized N-terminal ATP-binding domain (targeted by geldanamycin via Arg98 as a key selectivity residue) and a C-terminal nucleotide-binding site.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1118200 (PfHsp90) is an essential cytosolic molecular chaperone in Plasmodium falciparum that drives intra-erythrocytic development, with its inhibition arresting parasites at the ring-to-trophozoite transition [#0, #2]. It assembles into ~300 kDa hetero-oligomeric complexes together with PfHsp70 and additional co-chaperones and clients, an assembly disrupted by the Hsp90 inhibitor geldanamycin [#0, #2]. PfHop bridges PfHsp70 and PfHsp90 into a functional complex, with its TPR2A motif preferentially engaging the PfHsp90 C-terminus in a nucleotide-influenced manner [#7, #11], and PfHsp90 further recruits TPR-domain partners including the phosphatase PfPP5, the immunophilin PfFKBP35, and calcineurin [#5, #4, #3]. Biochemically, recombinant PfHsp90 possesses the highest ATPase activity among known Hsp90 proteins (~6-fold above human Hsp90) through a geldanamycin-sensitive N-terminal ATP-binding domain, in which Arg98 confers selectivity for parasite-directed inhibitors, and it additionally harbors a C-terminal nucleotide-binding site [#6, #1, #9, #16]. Its unusually large charged linker acts as a functional rheostat tuning chaperone activity and co-chaperone interaction, and an acetylation site overlapping the Aha1/p23 binding region modulates complex assembly [#8, #6]. Functionally, PfHsp90 stabilizes the client PfSir2A to maintain histone deacetylase activity and var gene silencing [#12], and directly chaperones the active 26S proteasome to sustain proteostasis [#13], establishing it as a hub linking chaperone function to gene regulation and protein turnover.\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that PfHsp90 is a single-copy, constitutively expressed and heat-inducible gene defined the parasite's core cytosolic chaperone and its unusual charged linker before any functional assay.\",\n      \"evidence\": \"Gene sequencing, Northern blot, and temperature-upshift analysis of pfhsp86; immunoprecipitation and monkey vaccination challenge\",\n      \"pmids\": [\"7838176\", \"8303938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No protein-level functional or chaperone assay in these studies\", \"ATP-binding inferred from sequence rather than measured directly\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying PfPP5 as a co-immunoprecipitating partner gave the first evidence that PfHsp90 organizes TPR-domain co-chaperones into a native complex.\",\n      \"evidence\": \"Co-immunoprecipitation of PfPP5 with native PfHsp90 from parasite lysates\",\n      \"pmids\": [\"11737864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP without reciprocal pulldown\", \"No in vitro reconstitution or functional consequence of the interaction\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that PfHsp90 forms ~300 kDa PfHsp70-containing complexes and that geldanamycin arrests development answered whether PfHsp90 is functionally essential for the intra-erythrocytic cycle.\",\n      \"evidence\": \"Sedimentation, SEC, GA inhibition, and flow cytometry in P. falciparum; recombinant ATP-binding assay with GA inhibition and ~20 nM growth IC50\",\n      \"pmids\": [\"12584193\", \"14514358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Client repertoire not defined\", \"Genetic (non-pharmacological) essentiality not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"W2\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that the PfHsp90 multi-chaperone complex mediates heat-shock cytoprotection linked the chaperone to temperature-dependent stage progression.\",\n      \"evidence\": \"Co-IP identifying PfHsp70, PfPP5, tubulin; GA complex disruption and heat-shock flow cytometry\",\n      \"pmids\": [\"15339915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of client stabilization during heat shock not resolved\", \"Role of tubulin association undefined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Adding calcineurin and PfFKBP35 as PfHsp90-associated partners expanded the co-chaperone network and rationalized drug synergy with the chaperone.\",\n      \"evidence\": \"Co-IP from parasite lysates, TPR-domain interaction, and GA/ascomycin/cyclosporin A synergy assays\",\n      \"pmids\": [\"15811524\", \"15850699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactions rest on single-method co-IP\", \"Functional requirement of each partner for chaperone cycle not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Quantifying PfHsp90's exceptionally high ATPase activity and mapping an acetylation site over the Aha1/p23 region tied catalytic output and PTM to co-chaperone assembly.\",\n      \"evidence\": \"In vitro ATPase assay with recombinant full-length protein, MS identification of acetylation, HDAC-inhibitor complex disruption\",\n      \"pmids\": [\"20837488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme responsible for acetylation not identified\", \"Physiological trigger for acetylation-dependent dissociation unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Chimeric-linker experiments in yeast established the charged linker as a functional rheostat, and SPR plus Arg98 mutagenesis defined the structural basis for parasite-selective ATP-site inhibition.\",\n      \"evidence\": \"Chimeric yeast Hsp90 constructs with ATPase/biophysical/in vivo assays; SPR harmine binding and Arg98 site-directed mutagenesis\",\n      \"pmids\": [\"22315411\", \"22615284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulators acting on the linker in parasites not identified\", \"Selectivity residue validation limited to specific ligands\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Domain-resolved PfHop mapping and imidazopyridazine target deconvolution refined how co-chaperones and inhibitors engage distinct PfHsp90 termini.\",\n      \"evidence\": \"Far Western, SPR, co-IP, split-GFP for PfHop domains; compound target deconvolution to the N-terminal ATP site\",\n      \"pmids\": [\"26267894\", \"26711771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nucleotide-dependence of PfHop switching not fully mechanistic\", \"Downstream clients of these ligand-bound states undefined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying PfSir2A as a stabilized client connected PfHsp90 chaperone activity to histone deacetylation and var gene silencing.\",\n      \"evidence\": \"Co-IP of PfHsp90-PfSir2A, 17-AAG/Radicicol inhibition, PfSir2A stability/HDAC-activity and var expression readouts\",\n      \"pmids\": [\"36121150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stabilization is direct folding or complex-mediated not fully dissected\", \"Breadth of PfHsp90-dependent epigenetic clients unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Thermal proteome profiling demonstrating PfHsp90-dependent 26S proteasome stability linked the chaperone directly to proteostasis and hydrolytic activity.\",\n      \"evidence\": \"Thermal proteome profiling, proteasome activity assays, and selective PfHsp90 inhibitors across life stages\",\n      \"pmids\": [\"38492573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface with the 26S proteasome not defined\", \"Which proteasome subunits are direct clients unclear\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Biochemical characterization of a C-terminal nucleotide-binding site added a second, selective nucleotide-interaction module beyond the N-terminal ATPase.\",\n      \"evidence\": \"Lysine-reactive nucleotide analog affinity, ATP resin, limited proteolysis, and mutagenesis on a C-terminal PfHsp90 truncation\",\n      \"pmids\": [\"40907219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the C-terminal site in the chaperone cycle not established\", \"Single-lab findings with limited mechanistic follow-up\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PfHsp90's two nucleotide-binding sites, charged-linker rheostat, and acetylation state are coordinated in vivo to select among its clients (PfSir2A, the 26S proteasome) and co-chaperones during the parasite cycle.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of the full PfHsp90 chaperone cycle in P. falciparum\", \"Complete client census undefined\", \"Regulatory inputs controlling complex composition unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051082\", \"supporting_discovery_ids\": [0, 2, 12, 13]},\n      {\"term_id\": \"GO:0005524\", \"supporting_discovery_ids\": [1, 9, 10, 16]},\n      {\"term_id\": \"GO:0016887\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0051087\", \"supporting_discovery_ids\": [4, 5, 7, 11]},\n      {\"term_id\": \"GO:0000774\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006457\", \"supporting_discovery_ids\": [2, 12, 13]},\n      {\"term_id\": \"GO:0034605\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"GO:0043161\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0031047\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"~300 kDa PfHsp90-PfHsp70 hetero-oligomeric chaperone complex\",\n      \"PfHsp70-PfHop-PfHsp90 complex\",\n      \"PfHsp90-PfSir2A complex\",\n      \"PfHsp90-26S proteasome chaperone assembly\"\n    ],\n    \"partners\": [\n      \"PfHsp70\",\n      \"PfHop\",\n      \"PfPP5\",\n      \"PfFKBP35\",\n      \"calcineurin (PP2B)\",\n      \"tubulin\",\n      \"PfSir2A\",\n      \"26S proteasome\"\n    ],\n    \"other_free_text\": [\n      \"Highest ATPase activity of any known Hsp90 (~6-fold above human Hsp90) [#6]\",\n      \"N-terminal ATP-binding domain targeted by geldanamycin, harmine, and imidazopyridazines; Arg98 confers parasite selectivity [#1, #9, #10]\",\n      \"Distinct C-terminal nucleotide-binding site interacting with ATP/dATP/ADP but not AMP or GTP [#16]\",\n      \"Charged linker acts as a functional rheostat for chaperone activity and co-chaperone interaction [#8, #14]\",\n      \"Acetylation site overlapping the Aha1/p23 binding domain modulates complex assembly [#6]\",\n      \"Essential for ring-to-trophozoite transition; genetic inhibition arrests intra-erythrocytic development [#0, #2]\",\n      \"Strongly immunogenic antigen in a monkey vaccination trial [#15]\",\n      \"PfGrp94 is a distinct ER-localized Hsp90 paralog, separable from cytosolic PfHsp90 (contextual, not PF3D7_1118200) [#17]\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1118200","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 18 of 18 cited papers name other catalogue genes (PF3D7_0708400, PF3D7_0818900, PF3D7_1355500). The summary may describe one of those genes."},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1118200","name":null,"product":"heat shock protein 90, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0929900","name":null,"product":"heat shock protein 90, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0915900","name":null,"product":"heat shock protein 90, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}