{"gene":"PF3D7_0708500","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":2003,"finding":"PfHsp90 forms ~300 kDa complexes (sedimentation coefficient ~11S) that contain PfHsp70; geldanamycin (GA) inhibits these complexes and arrests parasite growth at the ring-to-trophozoite transition, and GA selectively inhibits PfHsp90 phosphorylation in treated cultures.","method":"Sedimentation analysis, size exclusion chromatography, co-immunoprecipitation, homology modeling, parasite culture inhibition assay, metabolic labeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (sedimentation, SEC, co-IP, phosphorylation assay) combined with functional inhibitor studies, single lab but replicated internally across methods","pmids":["12584193"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":1994,"finding":"The PfHsp90 (pfhsp86) gene is encoded by two exons separated by an 0.8-kb intron; it is expressed constitutively in both trophozoite and gametocyte stages, is a single-copy gene, and its transcript is upregulated 2–4-fold at elevated temperatures (39–41°C). The encoded protein contains an unusually large charged region with homology to the calreticulin calcium-binding domain.","method":"cDNA/gene sequencing, Northern blot (heat-shock transcription induction), chromosomal mapping, sequence analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct sequencing and Northern blot characterization, single lab, two orthogonal methods","pmids":["7828879"],"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; the protein is expressed at all erythrocytic stages, with relatively lower amounts in schizonts.","method":"Recombinant protein expression, ATP-binding assay, immunoblot of stage-specific lysates","journal":"Malaria journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro ATP-binding assay with specific inhibitor, single lab, two orthogonal methods","pmids":["14514358"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7, W2"}]},{"year":2004,"finding":"The PfHsp90 multi-chaperone complex (containing PfHsp70, PfPP5, and tubulin) is disrupted by geldanamycin, and this disruption attenuates heat shock-mediated promotion of parasite ring-to-trophozoite progression, establishing PfHsp90 as essential for temperature-dependent parasite development.","method":"Co-immunoprecipitation, flow cytometry (parasite stage quantification), geldanamycin inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifying complex components combined with functional flow cytometry readout, replicated across multiple temperature conditions, multiple orthogonal methods","pmids":["15339915"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"PfHsp90 physically associates with PfPP5 (a serine/threonine phosphatase) in vivo, as demonstrated by co-immunoprecipitation.","method":"Co-immunoprecipitation from parasite lysate","journal":"BMC microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP experiment, single lab, corroborated by the functional complex finding in a separate study","pmids":["11737864"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"PfHsp90 associates with PfFKBP35 via the TPR domain of FKBP35; geldanamycin (Hsp90 inhibitor) and ascomycin (FKBP35 inhibitor) inhibit P. falciparum growth synergistically.","method":"Co-immunoprecipitation, synergy inhibition assay in parasite culture","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP plus functional synergy assay, single lab","pmids":["15850699"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"Parasitic calcineurin (PP2B) associates with PfHsp90 in vivo; geldanamycin disrupts this association without affecting cyclosporin A sensitivity, establishing PfHsp90 as a component of the calcineurin complex.","method":"Co-immunoprecipitation, GA treatment disruption assay, in vitro phosphatase activity assay","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP with GA-disruption follow-up, single lab","pmids":["15811524"],"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), and GA inhibits PfHsp90 ATPase more robustly than human Hsp90. Mass spectrometry identified an acetylation site overlapping the Aha1/p23 binding domain; histone deacetylase inhibitor treatment caused partial dissociation of the PfHsp90 complex.","method":"In vitro ATPase assay (recombinant full-length protein), mass spectrometry (acetylation site), histone deacetylase inhibitor treatment + co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted ATPase activity measured with full-length recombinant protein, MS-identified PTM, and functional complex dissociation experiment, multiple orthogonal methods in one study","pmids":["20837488"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"PfHop (Hsp70-Hsp90 organising protein) co-localises with PfHsp90 and PfHsp70 in the trophozoite-stage cytosol, and is present in a complex with both chaperones as shown by gel filtration and co-immunoprecipitation.","method":"Immunofluorescence co-localisation, gel filtration chromatography, co-immunoprecipitation","journal":"Cell stress & chaperones","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP supported by gel filtration and co-localisation, single lab, multiple methods","pmids":["22005844"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"When the plasmodium native charged linker of PfHsp90 was introduced into yeast Hsp90 in place of the yeast linker, it affected ATPase activity, cochaperone interaction, and conformation in vitro and chaperone function in vivo, demonstrating that the linker sequence (not just length) is a functional determinant of Hsp90 activity.","method":"Chimeric yeast Hsp90 constructs with plasmodium linkers, in vitro ATPase assay, biophysical characterisation, in vivo yeast complementation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro ATPase plus biophysical assays plus in vivo functional complementation with mutagenic linker swaps, multiple orthogonal methods","pmids":["22315411"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"Site-directed mutagenesis of Arg98 in the PfHsp90 ATP-binding domain abolishes selective binding of harmine to PfHsp90 over human Hsp90, identifying Arg98 as a key residue for inhibitor selectivity.","method":"Site-directed mutagenesis, surface plasmon resonance (binding affinity measurement)","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis plus SPR, but single lab and single compound tested","pmids":["22615284"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"Class 2 imidazopyridazine compounds bind to the ATP-binding site of the N-terminal domain of PfHsp90, and PfHsp90 was identified as a binding partner of these class 2 compounds responsible for trophozoite-stage growth inhibition.","method":"Target identification (binding partner pulldown/MS), gatekeeper-mutant PKG parasite lines to rule out PKG as class 2 target, compound-Hsp90 binding characterisation","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — compound-target binding characterised and alternative targets ruled out by gatekeeper mutant parasites, single lab","pmids":["26711771"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"PfHop TPR2A subdomain preferentially interacts with the C-terminus of PfHsp90 (over PfHsp70-1), while TPR1 and TPR2B bind preferentially to PfHsp70-1; the PfHop–PfHsp90 interaction is direct and nucleotide-independent, as shown by far-Western, SPR, and split-GFP approaches.","method":"Far-Western blot, surface plasmon resonance, co-immunoprecipitation, split-GFP subdomain interaction assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — four orthogonal methods (far-Western, SPR, co-IP, split-GFP), multiple labs, direct binding characterised","pmids":["26267894"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PfHsp90 physically interacts with PfSir2A (a histone deacetylase), and inhibition of PfHsp90 with 17-AAG or Radicicol leads to depletion of PfSir2A protein and loss of its histone deacetylase activity, resulting in derepression of var genes and loss of ribosomal silencing.","method":"Co-immunoprecipitation, chemical inhibition (17-AAG, Radicicol), Western blot (protein stability), HDAC activity assay, gene expression analysis (var gene derepression)","journal":"mSphere","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus multiple functional readouts (protein stability, enzymatic activity, gene expression), multiple orthogonal methods, single lab","pmids":["36121150"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PfHsp90 directly promotes assembly and hydrolytic activity of the 26S proteasome; thermal proteome profiling upon PfHsp90 inhibition enriched proteasome subunits among destabilised proteins, and biochemical/cellular studies confirmed PfHsp90 chaperoning of the active 26S complex.","method":"Thermal proteome profiling, biochemical co-fractionation, cellular proteasome activity assays, selective PfHsp90 inhibitor (Tropane 1)","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — thermal proteome profiling combined with orthogonal biochemical and cellular studies, single lab but multiple methods","pmids":["38492573"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PfHsp90 exhibits in vitro ATPase activity and suppresses heat-induced aggregation of model substrates in a nucleotide-dependent manner (holdase chaperone activity); both activities are inhibited by NECA. Additionally, a C-terminal truncation of PfHsp90 specifically interacts with ATP (but not AMP or GTP) via an interaction requiring structural determinants identified by mutagenesis.","method":"ATPase assay, chaperone aggregation-suppression assay, affinity binding with lysine-reactive nucleotide analog and ATP resin, limited proteolysis, mutagenesis, molecular docking","journal":"Bioorganic & medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstituted enzymatic assays plus mutagenesis of C-terminal binding, but single lab and C-terminal binding not yet functionally validated in parasites","pmids":["40907219"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PfGrp94 (the ER-localised Hsp90 paralogue) is a distinct isoform from the cytosolic PfHsp90; it is localized in the endoplasmic reticulum. Plasmodium falciparum encodes four Hsp90 isoforms (cytosol, ER, mitochondria, apicoplast).","method":"Recombinant protein characterisation, ATPase assay, chaperone suppression assay, antiplasmodial assay","journal":"Proteins","confidence":"Low","confidence_rationale":"Tier 3 / Weak — characterisation of the ER paralogue (PfGrp94/PF3D7_0708500 is cytosolic; PfGrp94 is a different gene); this finding relates to family membership context, not PF3D7_0708500 itself","pmids":["39670568"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0708500 (PfHsp90/pfhsp86) is the major cytosolic Hsp90 of P. falciparum: it forms ~300 kDa hetero-oligomeric complexes with PfHsp70, PfPP5, calcineurin, PfFKBP35, and PfHop (bridged via the PfHop TPR2A–PfHsp90 C-terminus interaction); it has exceptionally high ATPase activity that is inhibited by geldanamycin; an acetylation site overlapping its Aha1/p23 co-chaperone binding domain modulates complex assembly; it is essential for the ring-to-trophozoite transition and for temperature-dependent parasite development; it chaperones PfSir2A to maintain its histone deacetylase activity and thereby regulate var gene silencing; and it directly promotes 26S proteasome assembly and activity, placing it at the hub of proteostasis in the intraerythrocytic parasite."},"narrative":{"mechanistic_narrative":"PF3D7_0708500 encodes PfHsp90, the major cytosolic Hsp90 chaperone of Plasmodium falciparum and a hub of intraerythrocytic proteostasis [PMID:12584193, PMID:15339915]. It assembles into ~300 kDa (~11S) hetero-oligomeric complexes containing PfHsp70, and geldanamycin disruption of these complexes arrests the parasite at the ring-to-trophozoite transition and blocks heat-shock-driven developmental progression, establishing PfHsp90 as essential for temperature-dependent development [PMID:12584193, PMID:15339915]. The chaperone possesses ATP-binding and exceptionally high ATPase activity — the highest among characterized Hsp90s and roughly six-fold above human Hsp90 — that is potently inhibited by geldanamycin, and it displays nucleotide-dependent holdase activity that suppresses substrate aggregation [PMID:14514358, PMID:20837488, PMID:40907219]. Its unusually long charged linker is itself a functional determinant of ATPase rate, co-chaperone interaction, and conformation [PMID:22315411], and an acetylation site overlapping the Aha1/p23 co-chaperone binding region modulates complex assembly [PMID:20837488]. PfHsp90 nucleates a co-chaperone network, associating with the phosphatase PfPP5, calcineurin, PfFKBP35 via its TPR domain, and PfHop through a direct, nucleotide-independent contact between the PfHop TPR2A subdomain and the PfHsp90 C-terminus [PMID:15339915, PMID:11737864, PMID:15850699, PMID:15811524, PMID:26267894]. Functionally, PfHsp90 chaperones PfSir2A to preserve its histone deacetylase activity and thereby maintain var gene and ribosomal silencing [PMID:36121150], and it directly promotes assembly and hydrolytic activity of the 26S proteasome [PMID:38492573]. Structural features including Arg98 in the ATP-binding pocket confer selectivity for parasite-directed inhibitors, making PfHsp90 an antimalarial drug target [PMID:22615284, PMID:26711771].","teleology":[{"year":1994,"claim":"Establishing the gene structure and expression behavior of pfhsp86 addressed whether the parasite's cytosolic Hsp90 is a stress-inducible single-copy chaperone.","evidence":"cDNA/gene sequencing, Northern blot heat-shock induction, and chromosomal mapping in P. falciparum","pmids":["7828879"],"confidence":"Medium","gaps":["Did not test chaperone or enzymatic function","Functional significance of the calreticulin-homologous charged region unaddressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"Identifying that PfHsp90 forms large PfHsp70-containing complexes whose geldanamycin inhibition arrests growth at the ring-to-trophozoite transition connected the chaperone to a specific, druggable developmental checkpoint.","evidence":"Sedimentation, SEC, co-IP, phosphorylation labeling, and parasite growth inhibition; plus recombinant ATP-binding assay in strains 3D7 and W2","pmids":["12584193","14514358"],"confidence":"High","gaps":["Kinase responsible for GA-sensitive phosphorylation not identified","Direct substrates of the chaperone complex not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium falciparum","strain":"3D7, W2"}]},{"year":2004,"claim":"Showing that GA-mediated disruption of the PfHsp90/PfHsp70/PfPP5/tubulin complex attenuates heat-driven ring-to-trophozoite progression established the chaperone as required for temperature-dependent development.","evidence":"Co-IP of complex components with flow-cytometric stage quantification across temperatures","pmids":["15339915"],"confidence":"High","gaps":["Individual contribution of each complex partner not dissected","Mechanism linking chaperone to the thermal checkpoint unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"Mapping physical partners (PfPP5, PfFKBP35 via its TPR domain, calcineurin) defined PfHsp90 as the organizing center of a phosphatase/immunophilin co-chaperone network and revealed drug synergy.","evidence":"Co-IP from parasite lysate, GA-disruption, phosphatase assays, and geldanamycin/ascomycin synergy in culture","pmids":["11737864","15850699","15811524"],"confidence":"Medium","gaps":["Single co-IP experiments without reciprocal validation for most partners","Functional consequence of each association for client processing not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"Quantifying PfHsp90's exceptionally high ATPase activity and identifying an acetylation site overlapping the Aha1/p23 domain linked its enzymatic power and a PTM to complex assembly and drug sensitivity.","evidence":"Full-length recombinant ATPase assays, mass spectrometry PTM mapping, and HDAC-inhibitor-induced complex dissociation","pmids":["20837488"],"confidence":"High","gaps":["Enzyme responsible for the acetylation not identified","Structural basis for the higher-than-human ATPase rate not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Demonstrating that the parasite charged linker is a functional determinant and that Arg98 governs inhibitor selectivity provided structural rationale for parasite-selective Hsp90 targeting.","evidence":"Chimeric yeast Hsp90 linker swaps with ATPase/biophysical/complementation assays, and site-directed mutagenesis with SPR","pmids":["22315411","22615284"],"confidence":"High","gaps":["Linker mechanism tested in yeast context rather than native parasite","Selectivity residue validated for a single compound (harmine)"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"Resolving the direct, subdomain-specific PfHop TPR2A–PfHsp90 C-terminal interaction and identifying PfHsp90 as the class 2 imidazopyridazine target refined both the co-chaperone architecture and druggability.","evidence":"Far-Western, SPR, co-IP, split-GFP for the Hop interaction; compound pulldown and PKG gatekeeper-mutant controls for target ID","pmids":["26267894","26711771"],"confidence":"High","gaps":["Functional consequence of Hop-mediated bridging for specific clients not shown","Whether class 2 binding phenocopies ATPase inhibition not fully established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Establishing that PfHsp90 chaperones PfSir2A to sustain its deacetylase activity connected the chaperone to epigenetic var gene and ribosomal silencing.","evidence":"Reciprocal co-IP, chemical inhibition (17-AAG, Radicicol), protein-stability Westerns, HDAC activity assays, and var gene expression analysis","pmids":["36121150"],"confidence":"High","gaps":["Direct chaperone-client folding mechanism for PfSir2A not reconstituted","Breadth of PfHsp90-dependent epigenetic clients unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Showing that PfHsp90 directly promotes 26S proteasome assembly and activity, alongside confirmation of nucleotide-dependent holdase activity, placed the chaperone at the center of parasite proteostasis and degradation.","evidence":"Thermal proteome profiling with a selective inhibitor, co-fractionation and proteasome activity assays, plus in vitro ATPase/aggregation-suppression and C-terminal nucleotide-binding mutagenesis","pmids":["38492573","40907219"],"confidence":"High","gaps":["Mechanism of proteasome subunit chaperoning not structurally defined","C-terminal nucleotide-binding determinants not yet validated in parasites"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How PfHsp90's co-chaperone network, PTMs, and client repertoire are integrated to control the developmental thermal checkpoint and epigenetic/proteostatic outputs remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No comprehensive parasite client interactome defined","Regulatory logic coupling ATPase cycle to specific client fates unknown","In vivo role of the charged linker in native parasites untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["~300 kDa PfHsp90-PfHsp70 multi-chaperone complex","PfHsp90-PfHsp70-PfPP5-tubulin complex","PfHsp90-PfHop-PfHsp70 complex","PfHsp90-calcineurin (PP2B) complex","26S proteasome (assembly chaperone)"],"partners":["PFHSP70","PFPP5","PFFKBP35","CALCINEURIN (PP2B)","PFHOP (TPR2A SUBDOMAIN)","PFSIR2A","TUBULIN"],"other_free_text":["Exceptionally high ATPase activity, ~6-fold above human Hsp90, potently inhibited by geldanamycin [#7]","Charged linker sequence is a functional determinant of ATPase, co-chaperone binding, and conformation [#9]","Acetylation site overlapping the Aha1/p23 binding domain modulates complex assembly [#7]","Arg98 in the ATP-binding domain confers parasite-selective inhibitor binding [#10]","Antimalarial drug target for geldanamycin, harmine, class 2 imidazopyridazines, 17-AAG, Radicicol, and Tropane 1 [#10, #11, #13, #14]","Essential for the ring-to-trophozoite transition and temperature-dependent development [#0, #3]","PfGrp94 is a distinct ER-localized Hsp90 paralogue, not this gene [#16]"]}},"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":190,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 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The encoded protein contains an unusually large charged region with homology to the calreticulin calcium-binding domain.\",\n      \"method\": \"cDNA/gene sequencing, Northern blot (heat-shock transcription induction), chromosomal mapping, sequence analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct sequencing and Northern blot characterization, single lab, two orthogonal methods\",\n      \"pmids\": [\"7828879\"],\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; the protein is expressed at all erythrocytic stages, with relatively lower amounts in schizonts.\",\n      \"method\": \"Recombinant protein expression, ATP-binding assay, immunoblot of stage-specific lysates\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro ATP-binding assay with specific inhibitor, single lab, two orthogonal methods\",\n      \"pmids\": [\"14514358\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7, W2\"}]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The PfHsp90 multi-chaperone complex (containing PfHsp70, PfPP5, and tubulin) is disrupted by geldanamycin, and this disruption attenuates heat shock-mediated promotion of parasite ring-to-trophozoite progression, establishing PfHsp90 as essential for temperature-dependent parasite development.\",\n      \"method\": \"Co-immunoprecipitation, flow cytometry (parasite stage quantification), geldanamycin inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifying complex components combined with functional flow cytometry readout, replicated across multiple temperature conditions, multiple orthogonal methods\",\n      \"pmids\": [\"15339915\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PfHsp90 physically associates with PfPP5 (a serine/threonine phosphatase) in vivo, as demonstrated by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation from parasite lysate\",\n      \"journal\": \"BMC microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP experiment, single lab, corroborated by the functional complex finding in a separate study\",\n      \"pmids\": [\"11737864\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PfHsp90 associates with PfFKBP35 via the TPR domain of FKBP35; geldanamycin (Hsp90 inhibitor) and ascomycin (FKBP35 inhibitor) inhibit P. falciparum growth synergistically.\",\n      \"method\": \"Co-immunoprecipitation, synergy inhibition assay in parasite culture\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP plus functional synergy assay, single lab\",\n      \"pmids\": [\"15850699\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Parasitic calcineurin (PP2B) associates with PfHsp90 in vivo; geldanamycin disrupts this association without affecting cyclosporin A sensitivity, establishing PfHsp90 as a component of the calcineurin complex.\",\n      \"method\": \"Co-immunoprecipitation, GA treatment disruption assay, in vitro phosphatase activity assay\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP with GA-disruption follow-up, single lab\",\n      \"pmids\": [\"15811524\"],\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), and GA inhibits PfHsp90 ATPase more robustly than human Hsp90. Mass spectrometry identified an acetylation site overlapping the Aha1/p23 binding domain; histone deacetylase inhibitor treatment caused partial dissociation of the PfHsp90 complex.\",\n      \"method\": \"In vitro ATPase assay (recombinant full-length protein), mass spectrometry (acetylation site), histone deacetylase inhibitor treatment + co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted ATPase activity measured with full-length recombinant protein, MS-identified PTM, and functional complex dissociation experiment, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20837488\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PfHop (Hsp70-Hsp90 organising protein) co-localises with PfHsp90 and PfHsp70 in the trophozoite-stage cytosol, and is present in a complex with both chaperones as shown by gel filtration and co-immunoprecipitation.\",\n      \"method\": \"Immunofluorescence co-localisation, gel filtration chromatography, co-immunoprecipitation\",\n      \"journal\": \"Cell stress & chaperones\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP supported by gel filtration and co-localisation, single lab, multiple methods\",\n      \"pmids\": [\"22005844\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"When the plasmodium native charged linker of PfHsp90 was introduced into yeast Hsp90 in place of the yeast linker, it affected ATPase activity, cochaperone interaction, and conformation in vitro and chaperone function in vivo, demonstrating that the linker sequence (not just length) is a functional determinant of Hsp90 activity.\",\n      \"method\": \"Chimeric yeast Hsp90 constructs with plasmodium linkers, in vitro ATPase assay, biophysical characterisation, in vivo yeast complementation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro ATPase plus biophysical assays plus in vivo functional complementation with mutagenic linker swaps, multiple orthogonal methods\",\n      \"pmids\": [\"22315411\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Site-directed mutagenesis of Arg98 in the PfHsp90 ATP-binding domain abolishes selective binding of harmine to PfHsp90 over human Hsp90, identifying Arg98 as a key residue for inhibitor selectivity.\",\n      \"method\": \"Site-directed mutagenesis, surface plasmon resonance (binding affinity measurement)\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis plus SPR, but single lab and single compound tested\",\n      \"pmids\": [\"22615284\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Class 2 imidazopyridazine compounds bind to the ATP-binding site of the N-terminal domain of PfHsp90, and PfHsp90 was identified as a binding partner of these class 2 compounds responsible for trophozoite-stage growth inhibition.\",\n      \"method\": \"Target identification (binding partner pulldown/MS), gatekeeper-mutant PKG parasite lines to rule out PKG as class 2 target, compound-Hsp90 binding characterisation\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — compound-target binding characterised and alternative targets ruled out by gatekeeper mutant parasites, single lab\",\n      \"pmids\": [\"26711771\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PfHop TPR2A subdomain preferentially interacts with the C-terminus of PfHsp90 (over PfHsp70-1), while TPR1 and TPR2B bind preferentially to PfHsp70-1; the PfHop–PfHsp90 interaction is direct and nucleotide-independent, as shown by far-Western, SPR, and split-GFP approaches.\",\n      \"method\": \"Far-Western blot, surface plasmon resonance, co-immunoprecipitation, split-GFP subdomain 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), multiple labs, direct binding characterised\",\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 (a histone deacetylase), and inhibition of PfHsp90 with 17-AAG or Radicicol leads to depletion of PfSir2A protein and loss of its histone deacetylase activity, resulting in derepression of var genes and loss of ribosomal silencing.\",\n      \"method\": \"Co-immunoprecipitation, chemical inhibition (17-AAG, Radicicol), Western blot (protein stability), HDAC activity assay, gene expression analysis (var gene derepression)\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus multiple functional readouts (protein stability, enzymatic activity, gene expression), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36121150\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfHsp90 directly promotes assembly and hydrolytic activity of the 26S proteasome; thermal proteome profiling upon PfHsp90 inhibition enriched proteasome subunits among destabilised proteins, and biochemical/cellular studies confirmed PfHsp90 chaperoning of the active 26S complex.\",\n      \"method\": \"Thermal proteome profiling, biochemical co-fractionation, cellular proteasome activity assays, selective PfHsp90 inhibitor (Tropane 1)\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — thermal proteome profiling combined with orthogonal biochemical and cellular studies, single lab but multiple methods\",\n      \"pmids\": [\"38492573\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfHsp90 exhibits in vitro ATPase activity and suppresses heat-induced aggregation of model substrates in a nucleotide-dependent manner (holdase chaperone activity); both activities are inhibited by NECA. Additionally, a C-terminal truncation of PfHsp90 specifically interacts with ATP (but not AMP or GTP) via an interaction requiring structural determinants identified by mutagenesis.\",\n      \"method\": \"ATPase assay, chaperone aggregation-suppression assay, affinity binding with lysine-reactive nucleotide analog and ATP resin, limited proteolysis, mutagenesis, molecular docking\",\n      \"journal\": \"Bioorganic & medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstituted enzymatic assays plus mutagenesis of C-terminal binding, but single lab and C-terminal binding not yet functionally validated in parasites\",\n      \"pmids\": [\"40907219\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfGrp94 (the ER-localised Hsp90 paralogue) is a distinct isoform from the cytosolic PfHsp90; it is localized in the endoplasmic reticulum. Plasmodium falciparum encodes four Hsp90 isoforms (cytosol, ER, mitochondria, apicoplast).\",\n      \"method\": \"Recombinant protein characterisation, ATPase assay, chaperone suppression assay, antiplasmodial assay\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — characterisation of the ER paralogue (PfGrp94/PF3D7_0708500 is cytosolic; PfGrp94 is a different gene); this finding relates to family membership context, not PF3D7_0708500 itself\",\n      \"pmids\": [\"39670568\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0708500 (PfHsp90/pfhsp86) is the major cytosolic Hsp90 of P. falciparum: it forms ~300 kDa hetero-oligomeric complexes with PfHsp70, PfPP5, calcineurin, PfFKBP35, and PfHop (bridged via the PfHop TPR2A–PfHsp90 C-terminus interaction); it has exceptionally high ATPase activity that is inhibited by geldanamycin; an acetylation site overlapping its Aha1/p23 co-chaperone binding domain modulates complex assembly; it is essential for the ring-to-trophozoite transition and for temperature-dependent parasite development; it chaperones PfSir2A to maintain its histone deacetylase activity and thereby regulate var gene silencing; and it directly promotes 26S proteasome assembly and activity, placing it at the hub of proteostasis in the intraerythrocytic parasite.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0708500 encodes PfHsp90, the major cytosolic Hsp90 chaperone of Plasmodium falciparum and a hub of intraerythrocytic proteostasis [#0, #3]. It assembles into ~300 kDa (~11S) hetero-oligomeric complexes containing PfHsp70, and geldanamycin disruption of these complexes arrests the parasite at the ring-to-trophozoite transition and blocks heat-shock-driven developmental progression, establishing PfHsp90 as essential for temperature-dependent development [#0, #3]. The chaperone possesses ATP-binding and exceptionally high ATPase activity — the highest among characterized Hsp90s and roughly six-fold above human Hsp90 — that is potently inhibited by geldanamycin, and it displays nucleotide-dependent holdase activity that suppresses substrate aggregation [#2, #7, #15]. Its unusually long charged linker is itself a functional determinant of ATPase rate, co-chaperone interaction, and conformation [#9], and an acetylation site overlapping the Aha1/p23 co-chaperone binding region modulates complex assembly [#7]. PfHsp90 nucleates a co-chaperone network, associating with the phosphatase PfPP5, calcineurin, PfFKBP35 via its TPR domain, and PfHop through a direct, nucleotide-independent contact between the PfHop TPR2A subdomain and the PfHsp90 C-terminus [#3, #4, #5, #6, #12]. Functionally, PfHsp90 chaperones PfSir2A to preserve its histone deacetylase activity and thereby maintain var gene and ribosomal silencing [#13], and it directly promotes assembly and hydrolytic activity of the 26S proteasome [#14]. Structural features including Arg98 in the ATP-binding pocket confer selectivity for parasite-directed inhibitors, making PfHsp90 an antimalarial drug target [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the gene structure and expression behavior of pfhsp86 addressed whether the parasite's cytosolic Hsp90 is a stress-inducible single-copy chaperone.\",\n      \"evidence\": \"cDNA/gene sequencing, Northern blot heat-shock induction, and chromosomal mapping in P. falciparum\",\n      \"pmids\": [\"7828879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not test chaperone or enzymatic function\", \"Functional significance of the calreticulin-homologous charged region unaddressed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying that PfHsp90 forms large PfHsp70-containing complexes whose geldanamycin inhibition arrests growth at the ring-to-trophozoite transition connected the chaperone to a specific, druggable developmental checkpoint.\",\n      \"evidence\": \"Sedimentation, SEC, co-IP, phosphorylation labeling, and parasite growth inhibition; plus recombinant ATP-binding assay in strains 3D7 and W2\",\n      \"pmids\": [\"12584193\", \"14514358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for GA-sensitive phosphorylation not identified\", \"Direct substrates of the chaperone complex not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7, W2\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that GA-mediated disruption of the PfHsp90/PfHsp70/PfPP5/tubulin complex attenuates heat-driven ring-to-trophozoite progression established the chaperone as required for temperature-dependent development.\",\n      \"evidence\": \"Co-IP of complex components with flow-cytometric stage quantification across temperatures\",\n      \"pmids\": [\"15339915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of each complex partner not dissected\", \"Mechanism linking chaperone to the thermal checkpoint unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapping physical partners (PfPP5, PfFKBP35 via its TPR domain, calcineurin) defined PfHsp90 as the organizing center of a phosphatase/immunophilin co-chaperone network and revealed drug synergy.\",\n      \"evidence\": \"Co-IP from parasite lysate, GA-disruption, phosphatase assays, and geldanamycin/ascomycin synergy in culture\",\n      \"pmids\": [\"11737864\", \"15850699\", \"15811524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP experiments without reciprocal validation for most partners\", \"Functional consequence of each association for client processing not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Quantifying PfHsp90's exceptionally high ATPase activity and identifying an acetylation site overlapping the Aha1/p23 domain linked its enzymatic power and a PTM to complex assembly and drug sensitivity.\",\n      \"evidence\": \"Full-length recombinant ATPase assays, mass spectrometry PTM mapping, and HDAC-inhibitor-induced complex dissociation\",\n      \"pmids\": [\"20837488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme responsible for the acetylation not identified\", \"Structural basis for the higher-than-human ATPase rate not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that the parasite charged linker is a functional determinant and that Arg98 governs inhibitor selectivity provided structural rationale for parasite-selective Hsp90 targeting.\",\n      \"evidence\": \"Chimeric yeast Hsp90 linker swaps with ATPase/biophysical/complementation assays, and site-directed mutagenesis with SPR\",\n      \"pmids\": [\"22315411\", \"22615284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Linker mechanism tested in yeast context rather than native parasite\", \"Selectivity residue validated for a single compound (harmine)\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolving the direct, subdomain-specific PfHop TPR2A\\u2013PfHsp90 C-terminal interaction and identifying PfHsp90 as the class 2 imidazopyridazine target refined both the co-chaperone architecture and druggability.\",\n      \"evidence\": \"Far-Western, SPR, co-IP, split-GFP for the Hop interaction; compound pulldown and PKG gatekeeper-mutant controls for target ID\",\n      \"pmids\": [\"26267894\", \"26711771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Hop-mediated bridging for specific clients not shown\", \"Whether class 2 binding phenocopies ATPase inhibition not fully established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Establishing that PfHsp90 chaperones PfSir2A to sustain its deacetylase activity connected the chaperone to epigenetic var gene and ribosomal silencing.\",\n      \"evidence\": \"Reciprocal co-IP, chemical inhibition (17-AAG, Radicicol), protein-stability Westerns, HDAC activity assays, and var gene expression analysis\",\n      \"pmids\": [\"36121150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chaperone-client folding mechanism for PfSir2A not reconstituted\", \"Breadth of PfHsp90-dependent epigenetic clients unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that PfHsp90 directly promotes 26S proteasome assembly and activity, alongside confirmation of nucleotide-dependent holdase activity, placed the chaperone at the center of parasite proteostasis and degradation.\",\n      \"evidence\": \"Thermal proteome profiling with a selective inhibitor, co-fractionation and proteasome activity assays, plus in vitro ATPase/aggregation-suppression and C-terminal nucleotide-binding mutagenesis\",\n      \"pmids\": [\"38492573\", \"40907219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of proteasome subunit chaperoning not structurally defined\", \"C-terminal nucleotide-binding determinants not yet validated in parasites\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PfHsp90's co-chaperone network, PTMs, and client repertoire are integrated to control the developmental thermal checkpoint and epigenetic/proteostatic outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No comprehensive parasite client interactome defined\", \"Regulatory logic coupling ATPase cycle to specific client fates unknown\", \"In vivo role of the charged linker in native parasites untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016887\", \"supporting_discovery_ids\": [7, 9, 15]},\n      {\"term_id\": \"GO:0005524\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"GO:0051082\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0051087\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0043022\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006457\", \"supporting_discovery_ids\": [0, 3, 15]},\n      {\"term_id\": \"GO:0043248\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0009408\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0016568\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"~300 kDa PfHsp90-PfHsp70 multi-chaperone complex\",\n      \"PfHsp90-PfHsp70-PfPP5-tubulin complex\",\n      \"PfHsp90-PfHop-PfHsp70 complex\",\n      \"PfHsp90-calcineurin (PP2B) complex\",\n      \"26S proteasome (assembly chaperone)\"\n    ],\n    \"partners\": [\n      \"PfHsp70\",\n      \"PfPP5\",\n      \"PfFKBP35\",\n      \"calcineurin (PP2B)\",\n      \"PfHop (TPR2A subdomain)\",\n      \"PfSir2A\",\n      \"tubulin\"\n    ],\n    \"other_free_text\": [\n      \"Exceptionally high ATPase activity, ~6-fold above human Hsp90, potently inhibited by geldanamycin [#7]\",\n      \"Charged linker sequence is a functional determinant of ATPase, co-chaperone binding, and conformation [#9]\",\n      \"Acetylation site overlapping the Aha1/p23 binding domain modulates complex assembly [#7]\",\n      \"Arg98 in the ATP-binding domain confers parasite-selective inhibitor binding [#10]\",\n      \"Antimalarial drug target for geldanamycin, harmine, class 2 imidazopyridazines, 17-AAG, Radicicol, and Tropane 1 [#10, #11, #13, #14]\",\n      \"Essential for the ring-to-trophozoite transition and temperature-dependent development [#0, #3]\",\n      \"PfGrp94 is a distinct ER-localized Hsp90 paralogue, not this gene [#16]\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_0708500","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 17 of 17 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_0708500","name":null,"product":"heat shock protein 86 family protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1219000","name":null,"product":"heat shock protein 90, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0107100","name":null,"product":"heat shock protein 86 family, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}