{"gene":"PF3D7_1443900","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2003,"finding":"PfHsp90 exists in ~300 kDa, 11S complexes that contain PfHsp70; geldanamycin (GA) inhibits PfHsp90 and arrests parasite development at ring-to-trophozoite transition; GA selectively inhibits PfHsp90 phosphorylation; pre-exposure to heat shock attenuates GA-mediated growth inhibition, consistent with a role for PfHsp90 in cytoprotection.","method":"Sedimentation analysis, size exclusion chromatography, homology modeling of GA-binding pocket, flow cytometry of parasite stages, metabolic labeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical fractionation identifying complex components, multiple orthogonal methods (sedimentation, gel filtration, stage-specific growth assays, phosphorylation analysis), replicated in subsequent studies","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; mRNA is mainly expressed in ring and trophozoite stages but protein is present in all erythrocytic stages.","method":"Recombinant protein expression, in vitro ATP-binding assay, geldanamycin competition, stage-specific Western blot","journal":"Malaria journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay on recombinant protein with defined inhibitor, single lab, single method for ATP-binding","pmids":["14514358"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"W2"}]},{"year":2004,"finding":"PfHsp90 multi-chaperone complex (containing PfHsp70, PfPP5, and tubulin) mediates heat shock-dependent cytoprotection and growth promotion during febrile episodes; geldanamycin disrupts this complex and inhibits ring-to-trophozoite progression in a temperature-dependent manner.","method":"Co-immunoprecipitation identifying complex components, flow cytometry of parasite stage progression, geldanamycin-mediated complex disruption","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP identifying multiple complex partners, functional stage-specific assays, replicated findings from same group","pmids":["15339915"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2001,"finding":"Native PfHsp90 co-immunoprecipitates with PfPP5 (a tetratricopeptide repeat-containing serine/threonine phosphatase) in P. falciparum parasite extracts, establishing PfPP5 as a binding partner of PfHsp90.","method":"Co-immunoprecipitation of native proteins from parasite lysate","journal":"BMC microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP experiment, independently supported by subsequent complex studies","pmids":["11737864"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"Plasmodial calcineurin (protein phosphatase 2B) associates with PfHsp90 in vivo; geldanamycin inhibits this association; PfFKBP35 associates with PfHsp90 via its TPR domain; geldanamycin and ascomycin act synergistically to inhibit P. falciparum growth.","method":"Co-immunoprecipitation of native proteins, pharmacological disruption with geldanamycin, TPR domain interaction analysis","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of native complex components with two separate interactors validated by domain mapping, single lab","pmids":["15811524","15850699"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"Full-length recombinant PfHsp90 has the highest ATPase activity of all known Hsp90s (6-fold higher than human Hsp90); geldanamycin inhibits PfHsp90 ATPase activity more robustly than human Hsp90; a site of acetylation overlapping with the Aha1 and p23 binding domain was identified by mass spectrometry, and histone deacetylase inhibitor treatment causes partial dissociation of the PfHsp90 complex.","method":"In vitro ATPase assay on recombinant protein, geldanamycin competition, mass spectrometric identification of acetylation site, histone deacetylase inhibitor treatment with complex analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay on recombinant protein, MS identification of PTM site, functional consequence via complex disruption, multiple orthogonal methods","pmids":["20837488"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"Crystal structure of the N-terminal ATP-binding domain of PfHsp90 was solved in apo and ADP-bound states at 2.3 Å resolution, showing the principal drug-binding pocket and high structural similarity to human Hsp90.","method":"X-ray crystallography","journal":"Proteins","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.3 Å in two states (apo and ADP-bound), rigorous structural method","pmids":["20635416"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"PfHop co-localises with PfHsp70 and PfHsp90 in trophozoite-stage parasites; gel filtration and co-immunoprecipitation demonstrate PfHop is present in a complex with both PfHsp70 and PfHsp90, suggesting PfHop mediates their functional interaction.","method":"Immunofluorescence co-localization, gel filtration, co-immunoprecipitation","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and gel filtration supporting complex, co-localization providing functional context, single lab","pmids":["22005844"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"Recombinant Pfp23 suppresses citrate synthase aggregation (chaperone activity) and interacts with PfHsp90 to suppress its ATPase activity; site-directed mutagenesis identified residues K91, H93, W94, and K96 in Pfp23 as crucial for binding PfHsp90.","method":"In vitro aggregation suppression assay, ATPase inhibition assay, site-directed mutagenesis, modeling of protein complex","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical assays plus mutagenesis defining interaction residues, multiple orthogonal methods in single rigorous study","pmids":["20140477"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"The unusually extended charged linker of PfHsp90 was introduced into yeast Hsp90 and shown to affect ATPase activity, cochaperone interaction, and conformation, establishing that the linker sequence (not just length) modulates chaperone function.","method":"Chimeric yeast Hsp90 constructs with native/artificial linkers, in vitro ATPase assay, biophysical characterization, in vivo yeast complementation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis/chimeras validated in vivo, but findings are about the PfHsp90 linker function inferred via yeast system, single study","pmids":["22315411"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"Site-directed mutagenesis identified Arg98 in PfHsp90 as essential for selective binding of harmine (a beta-carboline alkaloid) to PfHsp90 over human Hsp90; harmine binding was confirmed by surface plasmon resonance (Kd = 40 µM).","method":"Surface plasmon resonance binding assay, site-directed mutagenesis","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — SPR binding measurement plus mutagenesis identifying key residue, single lab","pmids":["22615284"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"PfHsp90 was identified as a binding partner for class 2 imidazopyridazine compounds at its ATP-binding N-terminal domain; a representative compound bound the ATP-binding site as shown by structural and biochemical analysis, and these compounds inhibit trophozoite-stage parasite growth.","method":"Binding partner identification, structural/biochemical analysis of compound-PfHsp90 interaction, stage-specific parasite growth inhibition assay","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding partner identification with ATP-site structural evidence and phenotypic validation, single study","pmids":["26711771"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"PfHop directly associates with PfHsp70-1 in a nucleotide-dependent fashion (ADP promotes the interaction more than ATP); TPR1 and TPR2B subdomains of PfHop preferentially bind the C-terminus of PfHsp70-1, while the TPR2A motif preferentially interacts with the C-terminus of PfHsp90.","method":"Far Western analysis, surface plasmon resonance, co-immunoprecipitation, split-GFP approach for TPR subdomain interaction mapping","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (far Western, SPR, co-IP, split-GFP) mapping subdomain specificity of PfHsp90-PfHop interaction","pmids":["26267894"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"PfHsp90 inhibitors exhibit anti-Plasmodium activity at both liver and blood stages; time-course inhibition studies support a role for PfHsp90 in late liver-stage parasite development; PfHsp90 inhibitor SNX-0723 synergizes with PIK-75 to reduce liver-stage parasite load.","method":"Target-based compound binding screens, cell-based liver-stage and blood-stage malaria assays, time-course inhibition studies, expression analysis","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based assays across multiple life stages with time-course analysis, single lab","pmids":["29339390"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PfHsp90 physically interacts with PfSir2A (a histone deacetylase); inhibition of PfHsp90 by 17-AAG or radicicol results in depletion of PfSir2A protein and loss of its histone deacetylase activity, causing derepression of var genes and loss of ribosomal silencing. PfHsp90 thus acts as a chaperone required for PfSir2A stability.","method":"Co-immunoprecipitation of PfHsp90-PfSir2A complex, pharmacological inhibition (17-AAG, radicicol) with Western blot for PfSir2A levels, histone deacetylase activity assay, var gene expression analysis","journal":"mSphere","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP establishing direct interaction, functional consequence via enzymatic activity loss and gene derepression with two independent chemical inhibitors, multiple orthogonal readouts","pmids":["36121150"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Thermal proteome profiling following selective PfHsp90 inhibition identified the 26S proteasome as enriched among proteins with perturbed stability; subsequent biochemical and cellular studies support 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)","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased proteome-wide thermal profiling combined with targeted biochemical validation of proteasome interaction and activity, multiple orthogonal methods","pmids":["38492573"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"The C-terminus of PfHsp90 contains a specific nucleotide-binding site that interacts with ATP, dATP, and ADP (but not AMP or GTP), as shown by affinity experiments with a lysine-reactive nucleotide analog and an ATP resin; limited proteolysis and mutagenesis support this interaction at the C-terminal domain.","method":"Affinity experiments with lysine-reactive nucleotide analog and ATP resin, limited proteolysis, site-directed mutagenesis, computational analysis","journal":"Bioorganic & medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assays plus mutagenesis on recombinant C-terminal truncation, single lab, nucleotide selectivity characterized","pmids":["40907219"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"finding":"The PfHsp90 gene (pfhsp86) is constitutively expressed in both trophozoite and gametocyte stages; transcription is enhanced 2–4-fold at elevated temperatures (39–41°C); the protein is encoded by a single gene with two exons separated by an intron; the sequence contains an unusually large charged amino acid region homologous to the calreticulin calcium-binding domain; phylogenetic analysis places PfHsp90 closer to plant Hsp90 than to vertebrate or other parasite Hsp90s.","method":"Gene sequencing, Northern blot (stage-specific expression), phylogenetic analysis, sequence homology analysis","journal":"Molecular and biochemical parasitology / Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — molecular characterization by two independent groups with nucleotide sequencing and expression analysis, replicated findings","pmids":["7838176","3060854"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfHsp90 (PF3D7_1443900) is an essential cytosolic molecular chaperone whose N-terminal domain binds and hydrolyzes ATP (with the highest ATPase activity among known Hsp90s), forms ~300 kDa hetero-oligomeric complexes with PfHsp70, PfHop, PfPP5, PfFKBP35, and calcineurin (regulated by co-chaperones including p23/Pfp23 which suppresses its ATPase activity), directly chaperones client proteins including PfSir2A and the 26S proteasome to maintain their stability and activity, is regulated by acetylation at a site overlapping the Aha1/p23 binding domain, and is inhibited by geldanamycin and related compounds that arrest parasite growth by disrupting these chaperone complexes."},"narrative":{"mechanistic_narrative":"PF3D7_1443900 (PfHsp90) is an essential cytosolic molecular chaperone of Plasmodium falciparum that supports parasite survival and stage progression, and its inhibition arrests development at the ring-to-trophozoite transition [PMID:12584193, PMID:15339915]. It is an ATP-driven chaperone: its N-terminal domain binds and hydrolyzes ATP, displaying the highest ATPase activity of any known Hsp90 (~6-fold above human Hsp90), and a crystal structure of this domain in apo and ADP-bound states reveals the principal drug-binding pocket [PMID:14514358, PMID:20837488, PMID:20635416]. PfHsp90 assembles into ~300 kDa hetero-oligomeric complexes together with PfHsp70, the co-chaperone PfHop (whose TPR2A motif binds the PfHsp90 C-terminus), PfPP5, PfFKBP35, and calcineurin, with the ATPase cycle tuned by co-chaperones — Pfp23 suppresses ATPase activity via defined contact residues, and an acetylation site overlapping the Aha1/p23 binding surface modulates complex integrity [PMID:15339915, PMID:11737864, PMID:15811524, PMID:15850699, PMID:22005844, PMID:20140477, PMID:26267894]. Through these complexes PfHsp90 chaperones specific clients: it maintains the stability and histone deacetylase activity of PfSir2A, so its inhibition derepresses var genes and disrupts ribosomal silencing, and it promotes the hydrolytic activity of the 26S proteasome [PMID:36121150, PMID:38492573]. PfHsp90 is a validated antimalarial target inhibited by geldanamycin and structurally diverse compounds acting at the N-terminal ATP site, with activity across blood and liver stages [PMID:12584193, PMID:26711771, PMID:29339390]. Its distinctive extended charged linker further modulates ATPase activity and co-chaperone interaction, contributing to functional divergence from human Hsp90 [PMID:22315411].","teleology":[{"year":1994,"claim":"Establishing the gene structure and expression pattern was the first step in defining PfHsp90 as a stress-responsive, developmentally expressed chaperone gene.","evidence":"Gene sequencing, Northern blot, and phylogenetic analysis of pfhsp86 across parasite stages","pmids":["7838176","3060854"],"confidence":"Medium","gaps":["No protein-level function assayed","Charged-region and phylogenetic observations were sequence-based, not functional"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2001,"claim":"Native co-IP identified PfPP5 as the first physical binding partner of PfHsp90, opening the question of what larger complex PfHsp90 forms.","evidence":"Co-immunoprecipitation of native proteins from parasite lysate","pmids":["11737864"],"confidence":"Medium","gaps":["Single co-IP without reciprocal validation at the time","Functional consequence of the PfPP5 interaction not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"Fractionation and inhibitor studies defined PfHsp90 as an ATP-binding chaperone in a ~300 kDa PfHsp70-containing complex whose inhibition arrests specific developmental stages.","evidence":"Sedimentation/gel filtration, recombinant ATP-binding assay with geldanamycin competition, stage-specific growth assays","pmids":["12584193","14514358"],"confidence":"High","gaps":["ATPase turnover (not just binding) not yet quantified","Client proteins unidentified","Mechanistic basis of stage arrest unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium falciparum","strain":"W2"}]},{"year":2004,"claim":"Co-IP mapping of the multi-chaperone complex linked PfHsp90 function to heat shock-dependent cytoprotection during febrile temperature stress.","evidence":"Co-immunoprecipitation identifying PfHsp70/PfPP5/tubulin, temperature-dependent geldanamycin disruption and stage-progression assays","pmids":["15339915"],"confidence":"High","gaps":["Direct client substrates of the complex not defined","Role of tubulin association unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"Identification of calcineurin and PfFKBP35 (via TPR domain) as PfHsp90 associates expanded the interactome and revealed pharmacological synergy exploitable against the parasite.","evidence":"Native co-IP, TPR domain interaction analysis, geldanamycin/ascomycin synergy growth assays","pmids":["15811524","15850699"],"confidence":"Medium","gaps":["Whether these interactions are direct or bridged by other co-chaperones not resolved","Functional output of calcineurin/FKBP35 association unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"Enzymology, structure, and co-chaperone mapping converged to define the PfHsp90 ATPase cycle and its regulation, distinguishing it from human Hsp90.","evidence":"In vitro ATPase assays on recombinant protein, MS identification of an acetylation site in the Aha1/p23 domain, HDAC-inhibitor complex dissociation, N-domain crystal structure (apo/ADP), and Pfp23 mutagenesis defining binding residues","pmids":["20837488","20635416","20140477"],"confidence":"High","gaps":["Full-length conformational cycle not structurally resolved","Enzyme(s) writing/erasing the acetylation mark not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Chimeric and mutagenesis studies showed the parasite-specific charged linker and defined residues tune PfHsp90 activity and inhibitor selectivity, motivating selective drug design.","evidence":"Yeast Hsp90 linker-swap chimeras with ATPase/biophysical readout; SPR and mutagenesis defining Arg98 for harmine selectivity","pmids":["22315411","22615284"],"confidence":"Medium","gaps":["Linker function inferred through a heterologous yeast system rather than in parasite","Harmine affinity (Kd 40 µM) is modest"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"Subdomain mapping of PfHop and identification of ATP-site-binding chemotypes clarified how PfHsp90 is bridged to PfHsp70 and how it can be drugged at the N-terminus.","evidence":"Far Western, SPR, co-IP, split-GFP TPR mapping of PfHop; binding partner identification and structural analysis of imidazopyridazine compounds at the ATP site","pmids":["26267894","26711771"],"confidence":"High","gaps":["Stoichiometry and dynamics of the PfHsp70–PfHop–PfHsp90 relay not defined","Whether ATP-site inhibitors act identically in vivo not fully resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Cross-stage inhibitor profiling established PfHsp90 as a target relevant beyond blood stages, including late liver-stage development.","evidence":"Target-based binding screens, liver- and blood-stage cell assays, time-course inhibition, SNX-0723/PIK-75 synergy","pmids":["29339390"],"confidence":"Medium","gaps":["On-target versus off-target contribution of inhibitors not genetically confirmed","Liver-stage clients unidentified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Identification of PfSir2A as a stability-dependent client connected PfHsp90 chaperone function directly to epigenetic regulation of var genes and rRNA silencing.","evidence":"Co-IP of PfHsp90–PfSir2A, inhibitor-induced PfSir2A depletion (17-AAG, radicicol), HDAC activity assay, var gene expression analysis","pmids":["36121150"],"confidence":"High","gaps":["Whether PfSir2A folding/maturation requires the full co-chaperone cycle not dissected","Breadth of epigenetic clients beyond PfSir2A unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Unbiased thermal proteome profiling expanded the PfHsp90 client set to the 26S proteasome, linking the chaperone to regulated protein degradation.","evidence":"Thermal proteome profiling under selective inhibition plus biochemical proteasome activity assays (BX-2819, XL888, Tropane 1)","pmids":["38492573"],"confidence":"High","gaps":["Direct contact surface between PfHsp90 and proteasome subunits not mapped","Whether chaperoning is constitutive or stress-dependent unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Detection of a selective C-terminal nucleotide-binding site indicated PfHsp90 has a second regulatory ATP interaction beyond the canonical N-domain.","evidence":"Affinity experiments with lysine-reactive nucleotide analog and ATP resin, limited proteolysis, mutagenesis on C-terminal construct","pmids":["40907219"],"confidence":"Medium","gaps":["Functional/catalytic role of C-terminal nucleotide binding not established","No structure of the C-terminal site"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How the PfHsp90 ATPase cycle and its full co-chaperone network select and mature the complete client repertoire in vivo remains to be defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Comprehensive client census is incomplete beyond PfSir2A and the proteasome","No full-length or complex structure defining the working conformational cycle","Genetic (rather than pharmacological) dissection of essentiality and client dependence is lacking"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["~300 kDa PfHsp90 multi-chaperone complex (PfHsp90–PfHsp70–PfHop)","PfHsp90–PfPP5 complex","PfHsp90–PfHsp70–PfHop–PfPP5–PfFKBP35–calcineurin assembly","PfHsp90–PfSir2A complex","PfHsp90–26S proteasome"],"partners":["PFHSP70 / PFHSP70-1","PFHOP (TPR2A BINDS PFHSP90 C-TERMINUS)","PFPP5","PFFKBP35","CALCINEURIN (PP2B)","PFP23 (CO-CHAPERONE, ATPASE SUPPRESSOR)","PFSIR2A (CLIENT)","26S PROTEASOME (CLIENT)","TUBULIN"],"other_free_text":["N-terminal ATP-binding domain contains the principal drug-binding pocket; crystallized in apo and ADP-bound states [#6]","Highest ATPase activity among known Hsp90s (~6-fold over human) [#5]","Acetylation site overlapping the Aha1/p23 binding domain modulates complex integrity [#5]","Parasite-specific extended charged linker modulates ATPase activity, co-chaperone interaction, and conformation [#9]","Arg98 confers selective harmine binding over human Hsp90 [#10]","Distinct C-terminal nucleotide-binding site selective for ATP/dATP/ADP [#16]","Validated antimalarial target inhibited by geldanamycin, 17-AAG, radicicol, imidazopyridazines, and SNX-0723 across blood and liver stages [#0, #11, #13, #14]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"17125854","id":"PMC_17125854","title":"Genome-scale protein expression and structural biology of Plasmodium falciparum and related Apicomplexan organisms.","date":"2006","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/17125854","citation_count":198,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"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 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geldanamycin (GA) inhibits PfHsp90 and arrests parasite development at ring-to-trophozoite transition; GA selectively inhibits PfHsp90 phosphorylation; pre-exposure to heat shock attenuates GA-mediated growth inhibition, consistent with a role for PfHsp90 in cytoprotection.\",\n      \"method\": \"Sedimentation analysis, size exclusion chromatography, homology modeling of GA-binding pocket, flow cytometry of parasite stages, metabolic labeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical fractionation identifying complex components, multiple orthogonal methods (sedimentation, gel filtration, stage-specific growth assays, phosphorylation analysis), replicated in subsequent studies\",\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; mRNA is mainly expressed in ring and trophozoite stages but protein is present in all erythrocytic stages.\",\n      \"method\": \"Recombinant protein expression, in vitro ATP-binding assay, geldanamycin competition, stage-specific Western blot\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay on recombinant protein with defined inhibitor, single lab, single method for ATP-binding\",\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\": \"PfHsp90 multi-chaperone complex (containing PfHsp70, PfPP5, and tubulin) mediates heat shock-dependent cytoprotection and growth promotion during febrile episodes; geldanamycin disrupts this complex and inhibits ring-to-trophozoite progression in a temperature-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation identifying complex components, flow cytometry of parasite stage progression, geldanamycin-mediated complex disruption\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP identifying multiple complex partners, functional stage-specific assays, replicated findings from same group\",\n      \"pmids\": [\"15339915\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Native PfHsp90 co-immunoprecipitates with PfPP5 (a tetratricopeptide repeat-containing serine/threonine phosphatase) in P. falciparum parasite extracts, establishing PfPP5 as a binding partner of PfHsp90.\",\n      \"method\": \"Co-immunoprecipitation of native proteins from parasite lysate\",\n      \"journal\": \"BMC microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP experiment, independently supported by subsequent complex studies\",\n      \"pmids\": [\"11737864\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Plasmodial calcineurin (protein phosphatase 2B) associates with PfHsp90 in vivo; geldanamycin inhibits this association; PfFKBP35 associates with PfHsp90 via its TPR domain; geldanamycin and ascomycin act synergistically to inhibit P. falciparum growth.\",\n      \"method\": \"Co-immunoprecipitation of native proteins, pharmacological disruption with geldanamycin, TPR domain interaction analysis\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of native complex components with two separate interactors validated by domain mapping, single lab\",\n      \"pmids\": [\"15811524\", \"15850699\"],\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 of all known Hsp90s (6-fold higher than human Hsp90); geldanamycin inhibits PfHsp90 ATPase activity more robustly than human Hsp90; a site of acetylation overlapping with the Aha1 and p23 binding domain was identified by mass spectrometry, and histone deacetylase inhibitor treatment causes partial dissociation of the PfHsp90 complex.\",\n      \"method\": \"In vitro ATPase assay on recombinant protein, geldanamycin competition, mass spectrometric identification of acetylation site, histone deacetylase inhibitor treatment with complex analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay on recombinant protein, MS identification of PTM site, functional consequence via complex disruption, multiple orthogonal methods\",\n      \"pmids\": [\"20837488\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the N-terminal ATP-binding domain of PfHsp90 was solved in apo and ADP-bound states at 2.3 Å resolution, showing the principal drug-binding pocket and high structural similarity to human Hsp90.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.3 Å in two states (apo and ADP-bound), rigorous structural method\",\n      \"pmids\": [\"20635416\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PfHop co-localises with PfHsp70 and PfHsp90 in trophozoite-stage parasites; gel filtration and co-immunoprecipitation demonstrate PfHop is present in a complex with both PfHsp70 and PfHsp90, suggesting PfHop mediates their functional interaction.\",\n      \"method\": \"Immunofluorescence co-localization, gel filtration, co-immunoprecipitation\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and gel filtration supporting complex, co-localization providing functional context, single lab\",\n      \"pmids\": [\"22005844\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Recombinant Pfp23 suppresses citrate synthase aggregation (chaperone activity) and interacts with PfHsp90 to suppress its ATPase activity; site-directed mutagenesis identified residues K91, H93, W94, and K96 in Pfp23 as crucial for binding PfHsp90.\",\n      \"method\": \"In vitro aggregation suppression assay, ATPase inhibition assay, site-directed mutagenesis, modeling of protein complex\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical assays plus mutagenesis defining interaction residues, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"20140477\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The unusually extended charged linker of PfHsp90 was introduced into yeast Hsp90 and shown to affect ATPase activity, cochaperone interaction, and conformation, establishing that the linker sequence (not just length) modulates chaperone function.\",\n      \"method\": \"Chimeric yeast Hsp90 constructs with native/artificial linkers, in vitro ATPase assay, biophysical characterization, in vivo yeast complementation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis/chimeras validated in vivo, but findings are about the PfHsp90 linker function inferred via yeast system, single study\",\n      \"pmids\": [\"22315411\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Site-directed mutagenesis identified Arg98 in PfHsp90 as essential for selective binding of harmine (a beta-carboline alkaloid) to PfHsp90 over human Hsp90; harmine binding was confirmed by surface plasmon resonance (Kd = 40 µM).\",\n      \"method\": \"Surface plasmon resonance binding assay, site-directed mutagenesis\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR binding measurement plus mutagenesis identifying key residue, single lab\",\n      \"pmids\": [\"22615284\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PfHsp90 was identified as a binding partner for class 2 imidazopyridazine compounds at its ATP-binding N-terminal domain; a representative compound bound the ATP-binding site as shown by structural and biochemical analysis, and these compounds inhibit trophozoite-stage parasite growth.\",\n      \"method\": \"Binding partner identification, structural/biochemical analysis of compound-PfHsp90 interaction, stage-specific parasite growth inhibition assay\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding partner identification with ATP-site structural evidence and phenotypic validation, single study\",\n      \"pmids\": [\"26711771\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PfHop directly associates with PfHsp70-1 in a nucleotide-dependent fashion (ADP promotes the interaction more than ATP); TPR1 and TPR2B subdomains of PfHop preferentially bind the C-terminus of PfHsp70-1, while the TPR2A motif preferentially interacts with the C-terminus of PfHsp90.\",\n      \"method\": \"Far Western analysis, surface plasmon resonance, co-immunoprecipitation, split-GFP approach for TPR subdomain interaction mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (far Western, SPR, co-IP, split-GFP) mapping subdomain specificity of PfHsp90-PfHop interaction\",\n      \"pmids\": [\"26267894\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PfHsp90 inhibitors exhibit anti-Plasmodium activity at both liver and blood stages; time-course inhibition studies support a role for PfHsp90 in late liver-stage parasite development; PfHsp90 inhibitor SNX-0723 synergizes with PIK-75 to reduce liver-stage parasite load.\",\n      \"method\": \"Target-based compound binding screens, cell-based liver-stage and blood-stage malaria assays, time-course inhibition studies, expression analysis\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based assays across multiple life stages with time-course analysis, single lab\",\n      \"pmids\": [\"29339390\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PfHsp90 physically interacts with PfSir2A (a histone deacetylase); inhibition of PfHsp90 by 17-AAG or radicicol results in depletion of PfSir2A protein and loss of its histone deacetylase activity, causing derepression of var genes and loss of ribosomal silencing. PfHsp90 thus acts as a chaperone required for PfSir2A stability.\",\n      \"method\": \"Co-immunoprecipitation of PfHsp90-PfSir2A complex, pharmacological inhibition (17-AAG, radicicol) with Western blot for PfSir2A levels, histone deacetylase activity assay, var gene expression analysis\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP establishing direct interaction, functional consequence via enzymatic activity loss and gene derepression with two independent chemical inhibitors, multiple orthogonal readouts\",\n      \"pmids\": [\"36121150\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Thermal proteome profiling following selective PfHsp90 inhibition identified the 26S proteasome as enriched among proteins with perturbed stability; subsequent biochemical and cellular studies support 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)\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased proteome-wide thermal profiling combined with targeted biochemical validation of proteasome interaction and activity, multiple orthogonal methods\",\n      \"pmids\": [\"38492573\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The C-terminus of PfHsp90 contains a specific nucleotide-binding site that interacts with ATP, dATP, and ADP (but not AMP or GTP), as shown by affinity experiments with a lysine-reactive nucleotide analog and an ATP resin; limited proteolysis and mutagenesis support this interaction at the C-terminal domain.\",\n      \"method\": \"Affinity experiments with lysine-reactive nucleotide analog and ATP resin, limited proteolysis, site-directed mutagenesis, computational analysis\",\n      \"journal\": \"Bioorganic & medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assays plus mutagenesis on recombinant C-terminal truncation, single lab, nucleotide selectivity characterized\",\n      \"pmids\": [\"40907219\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The PfHsp90 gene (pfhsp86) is constitutively expressed in both trophozoite and gametocyte stages; transcription is enhanced 2–4-fold at elevated temperatures (39–41°C); the protein is encoded by a single gene with two exons separated by an intron; the sequence contains an unusually large charged amino acid region homologous to the calreticulin calcium-binding domain; phylogenetic analysis places PfHsp90 closer to plant Hsp90 than to vertebrate or other parasite Hsp90s.\",\n      \"method\": \"Gene sequencing, Northern blot (stage-specific expression), phylogenetic analysis, sequence homology analysis\",\n      \"journal\": \"Molecular and biochemical parasitology / Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — molecular characterization by two independent groups with nucleotide sequencing and expression analysis, replicated findings\",\n      \"pmids\": [\"7838176\", \"3060854\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfHsp90 (PF3D7_1443900) is an essential cytosolic molecular chaperone whose N-terminal domain binds and hydrolyzes ATP (with the highest ATPase activity among known Hsp90s), forms ~300 kDa hetero-oligomeric complexes with PfHsp70, PfHop, PfPP5, PfFKBP35, and calcineurin (regulated by co-chaperones including p23/Pfp23 which suppresses its ATPase activity), directly chaperones client proteins including PfSir2A and the 26S proteasome to maintain their stability and activity, is regulated by acetylation at a site overlapping the Aha1/p23 binding domain, and is inhibited by geldanamycin and related compounds that arrest parasite growth by disrupting these chaperone complexes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1443900 (PfHsp90) is an essential cytosolic molecular chaperone of Plasmodium falciparum that supports parasite survival and stage progression, and its inhibition arrests development at the ring-to-trophozoite transition [#0, #2]. It is an ATP-driven chaperone: its N-terminal domain binds and hydrolyzes ATP, displaying the highest ATPase activity of any known Hsp90 (~6-fold above human Hsp90), and a crystal structure of this domain in apo and ADP-bound states reveals the principal drug-binding pocket [#1, #5, #6]. PfHsp90 assembles into ~300 kDa hetero-oligomeric complexes together with PfHsp70, the co-chaperone PfHop (whose TPR2A motif binds the PfHsp90 C-terminus), PfPP5, PfFKBP35, and calcineurin, with the ATPase cycle tuned by co-chaperones — Pfp23 suppresses ATPase activity via defined contact residues, and an acetylation site overlapping the Aha1/p23 binding surface modulates complex integrity [#2, #3, #4, #7, #8, #12]. Through these complexes PfHsp90 chaperones specific clients: it maintains the stability and histone deacetylase activity of PfSir2A, so its inhibition derepresses var genes and disrupts ribosomal silencing, and it promotes the hydrolytic activity of the 26S proteasome [#14, #15]. PfHsp90 is a validated antimalarial target inhibited by geldanamycin and structurally diverse compounds acting at the N-terminal ATP site, with activity across blood and liver stages [#0, #11, #13]. Its distinctive extended charged linker further modulates ATPase activity and co-chaperone interaction, contributing to functional divergence from human Hsp90 [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the gene structure and expression pattern was the first step in defining PfHsp90 as a stress-responsive, developmentally expressed chaperone gene.\",\n      \"evidence\": \"Gene sequencing, Northern blot, and phylogenetic analysis of pfhsp86 across parasite stages\",\n      \"pmids\": [\"7838176\", \"3060854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No protein-level function assayed\", \"Charged-region and phylogenetic observations were sequence-based, not functional\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Native co-IP identified PfPP5 as the first physical binding partner of PfHsp90, opening the question of what larger complex PfHsp90 forms.\",\n      \"evidence\": \"Co-immunoprecipitation of native proteins from parasite lysate\",\n      \"pmids\": [\"11737864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP without reciprocal validation at the time\", \"Functional consequence of the PfPP5 interaction not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Fractionation and inhibitor studies defined PfHsp90 as an ATP-binding chaperone in a ~300 kDa PfHsp70-containing complex whose inhibition arrests specific developmental stages.\",\n      \"evidence\": \"Sedimentation/gel filtration, recombinant ATP-binding assay with geldanamycin competition, stage-specific growth assays\",\n      \"pmids\": [\"12584193\", \"14514358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ATPase turnover (not just binding) not yet quantified\", \"Client proteins unidentified\", \"Mechanistic basis of stage arrest unclear\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"W2\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Co-IP mapping of the multi-chaperone complex linked PfHsp90 function to heat shock-dependent cytoprotection during febrile temperature stress.\",\n      \"evidence\": \"Co-immunoprecipitation identifying PfHsp70/PfPP5/tubulin, temperature-dependent geldanamycin disruption and stage-progression assays\",\n      \"pmids\": [\"15339915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct client substrates of the complex not defined\", \"Role of tubulin association unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of calcineurin and PfFKBP35 (via TPR domain) as PfHsp90 associates expanded the interactome and revealed pharmacological synergy exploitable against the parasite.\",\n      \"evidence\": \"Native co-IP, TPR domain interaction analysis, geldanamycin/ascomycin synergy growth assays\",\n      \"pmids\": [\"15811524\", \"15850699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these interactions are direct or bridged by other co-chaperones not resolved\", \"Functional output of calcineurin/FKBP35 association unclear\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Enzymology, structure, and co-chaperone mapping converged to define the PfHsp90 ATPase cycle and its regulation, distinguishing it from human Hsp90.\",\n      \"evidence\": \"In vitro ATPase assays on recombinant protein, MS identification of an acetylation site in the Aha1/p23 domain, HDAC-inhibitor complex dissociation, N-domain crystal structure (apo/ADP), and Pfp23 mutagenesis defining binding residues\",\n      \"pmids\": [\"20837488\", \"20635416\", \"20140477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length conformational cycle not structurally resolved\", \"Enzyme(s) writing/erasing the acetylation mark not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Chimeric and mutagenesis studies showed the parasite-specific charged linker and defined residues tune PfHsp90 activity and inhibitor selectivity, motivating selective drug design.\",\n      \"evidence\": \"Yeast Hsp90 linker-swap chimeras with ATPase/biophysical readout; SPR and mutagenesis defining Arg98 for harmine selectivity\",\n      \"pmids\": [\"22315411\", \"22615284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Linker function inferred through a heterologous yeast system rather than in parasite\", \"Harmine affinity (Kd 40 µM) is modest\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Subdomain mapping of PfHop and identification of ATP-site-binding chemotypes clarified how PfHsp90 is bridged to PfHsp70 and how it can be drugged at the N-terminus.\",\n      \"evidence\": \"Far Western, SPR, co-IP, split-GFP TPR mapping of PfHop; binding partner identification and structural analysis of imidazopyridazine compounds at the ATP site\",\n      \"pmids\": [\"26267894\", \"26711771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of the PfHsp70–PfHop–PfHsp90 relay not defined\", \"Whether ATP-site inhibitors act identically in vivo not fully resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cross-stage inhibitor profiling established PfHsp90 as a target relevant beyond blood stages, including late liver-stage development.\",\n      \"evidence\": \"Target-based binding screens, liver- and blood-stage cell assays, time-course inhibition, SNX-0723/PIK-75 synergy\",\n      \"pmids\": [\"29339390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"On-target versus off-target contribution of inhibitors not genetically confirmed\", \"Liver-stage clients unidentified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of PfSir2A as a stability-dependent client connected PfHsp90 chaperone function directly to epigenetic regulation of var genes and rRNA silencing.\",\n      \"evidence\": \"Co-IP of PfHsp90–PfSir2A, inhibitor-induced PfSir2A depletion (17-AAG, radicicol), HDAC activity assay, var gene expression analysis\",\n      \"pmids\": [\"36121150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PfSir2A folding/maturation requires the full co-chaperone cycle not dissected\", \"Breadth of epigenetic clients beyond PfSir2A unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Unbiased thermal proteome profiling expanded the PfHsp90 client set to the 26S proteasome, linking the chaperone to regulated protein degradation.\",\n      \"evidence\": \"Thermal proteome profiling under selective inhibition plus biochemical proteasome activity assays (BX-2819, XL888, Tropane 1)\",\n      \"pmids\": [\"38492573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contact surface between PfHsp90 and proteasome subunits not mapped\", \"Whether chaperoning is constitutive or stress-dependent unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Detection of a selective C-terminal nucleotide-binding site indicated PfHsp90 has a second regulatory ATP interaction beyond the canonical N-domain.\",\n      \"evidence\": \"Affinity experiments with lysine-reactive nucleotide analog and ATP resin, limited proteolysis, mutagenesis on C-terminal construct\",\n      \"pmids\": [\"40907219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional/catalytic role of C-terminal nucleotide binding not established\", \"No structure of the C-terminal site\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the PfHsp90 ATPase cycle and its full co-chaperone network select and mature the complete client repertoire in vivo remains to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Comprehensive client census is incomplete beyond PfSir2A and the proteasome\", \"No full-length or complex structure defining the working conformational cycle\", \"Genetic (rather than pharmacological) dissection of essentiality and client dependence is lacking\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140662\", \"supporting_discovery_ids\": [0, 2, 8, 14, 15]},\n      {\"term_id\": \"GO:0005524\", \"supporting_discovery_ids\": [1, 6, 16]},\n      {\"term_id\": \"GO:0016887\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0051082\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006457\", \"supporting_discovery_ids\": [0, 2, 8, 14, 15]},\n      {\"term_id\": \"GO:0034605\", \"supporting_discovery_ids\": [0, 2, 17]},\n      {\"term_id\": \"GO:0043161\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\n      \"~300 kDa PfHsp90 multi-chaperone complex (PfHsp90–PfHsp70–PfHop)\",\n      \"PfHsp90–PfPP5 complex\",\n      \"PfHsp90–PfHsp70–PfHop–PfPP5–PfFKBP35–calcineurin assembly\",\n      \"PfHsp90–PfSir2A complex\",\n      \"PfHsp90–26S proteasome\"\n    ],\n    \"partners\": [\n      \"PfHsp70 / PfHsp70-1\",\n      \"PfHop (TPR2A binds PfHsp90 C-terminus)\",\n      \"PfPP5\",\n      \"PfFKBP35\",\n      \"calcineurin (PP2B)\",\n      \"Pfp23 (co-chaperone, ATPase suppressor)\",\n      \"PfSir2A (client)\",\n      \"26S proteasome (client)\",\n      \"tubulin\"\n    ],\n    \"other_free_text\": [\n      \"N-terminal ATP-binding domain contains the principal drug-binding pocket; crystallized in apo and ADP-bound states [#6]\",\n      \"Highest ATPase activity among known Hsp90s (~6-fold over human) [#5]\",\n      \"Acetylation site overlapping the Aha1/p23 binding domain modulates complex integrity [#5]\",\n      \"Parasite-specific extended charged linker modulates ATPase activity, co-chaperone interaction, and conformation [#9]\",\n      \"Arg98 confers selective harmine binding over human Hsp90 [#10]\",\n      \"Distinct C-terminal nucleotide-binding site selective for ATP/dATP/ADP [#16]\",\n      \"Validated antimalarial target inhibited by geldanamycin, 17-AAG, radicicol, imidazopyridazines, and SNX-0723 across blood and liver stages [#0, #11, #13, #14]\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1443900","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 19 of 20 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_1443900","name":null,"product":"heat shock protein 90, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1307800","name":null,"product":"heat shock protein 90, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1238400","name":null,"product":"heat shock protein 90, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}