Affinage · Plasmodium

PF3D7_0308500

activator of Hsp90 ATPase, putative

Audit flag: identity unverified
Annotated
2026-09-07
92 papers in source corpus 27 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PfHsp90 (PF3D7_0308500) is an essential ATP-dependent molecular chaperone of the intraerythrocytic malaria parasite whose inhibition arrests development at the ring-to-trophozoite transition and causes parasite death (PMID:12584193, PMID:15339915). The full-length recombinant protein exhibits the highest ATPase activity of any known Hsp90 orthologue—roughly six-fold that of human Hsp90—and is potently inhibited by geldanamycin (PMID:20837488); structural work shows it is an open, highly elongated and flexible homodimer whose N-terminal domain binds adenosine nucleotides in a Mg2+-dependent manner and whose C-terminal domain drives dimerization (PMID:32679196, PMID:20635416). PfHsp90 nucleates a cytosolic multi-chaperone machine, associating with PfHsp70, PfHop, the TPR-domain phosphatase PfPP5 and immunophilin PfFKBP35 (the latter docking onto the C-terminal MEEVD pentapeptide), and its ATPase cycle is tuned by co-chaperones—stimulated by PfAha1 and suppressed by Pfp23 and PfHop (PMID:15339915, PMID:22005844, PMID:19691130, PMID:22100910, PMID:20140477, PMID:31525467). Beyond canonical chaperoning, PfHsp90 directly promotes 26S proteasome hydrolysis (PMID:38492573) and has acquired nuclear regulatory roles at febrile temperatures: it acts as a transcriptional repressor of PfSIR2A/B by recruiting the H3K9me3 mark to their promoters and physically stabilizes PfSir2A protein and its histone deacetylase activity, thereby controlling var-gene silencing (PMID:33538363, PMID:36121150). Its own transcription is induced at febrile temperatures by the ApiAP2 factor PfAP2-HS (PMID:34400833), and the protein is displayed on the female gamete surface where it is required for fertilization (PMID:38131664). The conformational dynamics of its ATP-binding pocket differ from the human enzyme, a feature exploited to develop parasite-selective inhibitors (PMID:24580531, PMID:22615284).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 High

    Establishing that PfHsp90 is a genuine, druggable chaperone required showing it binds ATP, assembles into oligomeric complexes, and that its inhibition blocks a defined developmental step.

    Evidence ATP-binding and geldanamycin-inhibition assays on recombinant protein, plus sedimentation/SEC showing ~300 kDa Hsp70-containing complexes with stage-specific growth arrest in P. falciparum

    PMID:12584193 PMID:14514358

    Open questions at the time
    • Complex composition beyond Hsp70 not resolved at this stage
    • Direct client proteins not identified
  2. 2005 Medium

    The identity of the co-chaperones assembling on PfHsp90 was mapped by defining TPR-domain partners that dock the chaperone into functional complexes.

    Evidence Co-immunoprecipitation of native PfPP5, PfFKBP35 and PfCN with PfHsp90, with domain-deletion and synergy growth assays in P. falciparum

    PMID:11737864 PMID:15339915 PMID:15811524 PMID:15850699

    Open questions at the time
    • Whether these interactions are direct or bridged by other chaperones
    • Client proteins folded by the assembled complex unknown
  3. 2010 High

    Quantifying the enzymatic and structural properties revealed PfHsp90 as an unusually hyperactive ATPase with a defined N-terminal drug pocket, rationalizing its inhibitor sensitivity.

    Evidence In vitro ATPase assays on full-length recombinant protein, MS-based acetylation mapping, and a 2.3 Å crystal structure of the N-terminal domain in apo and ADP states

    PMID:20635416 PMID:20837488

    Open questions at the time
    • Full-length crystal structure not solved
    • Functional role of the acetylation site in vivo untested
  4. 2011 High

    Delineating how co-chaperones tune the ATPase cycle clarified the regulatory logic of the chaperone machine.

    Evidence SPR/NMR mapping of PfFKBP35-TPR binding the C-terminal MEEVD, plus reconstituted ATPase assays and mutagenesis showing Pfp23 suppresses and PfAha1 stimulates PfHsp90 ATPase in P. falciparum proteins

    PMID:19691130 PMID:20140477 PMID:22005844 PMID:22100910

    Open questions at the time
    • Order of co-chaperone loading during the catalytic cycle not established
    • In vivo consequences of ATPase modulation on client folding unknown
  5. 2014 High

    Demonstrating that PfHsp90's ATP-pocket dynamics differ from the human enzyme opened a route to parasite-selective inhibitors.

    Evidence SPR with harmine identifying Arg98 as a selectivity determinant, and structure-based design of 7-azaindoles binding only the parasite N-terminal domain, validated by yeast complementation and dynamics-altering mutants

    PMID:22615284 PMID:24580531

    Open questions at the time
    • Selectivity determinants not yet translated to in vivo efficacy in these studies
    • Impact on the assembled multi-chaperone complex not tested
  6. 2013 Medium

    Interactome profiling linked PfHsp90 to drug-resistance machinery, connecting chaperone function to chloroquine action.

    Evidence LC-MS/MS pulldown identifying PfCRT association and PU-H71/chloroquine synergy in P. falciparum in vitro and a P. berghei mouse model

    PMID:24098696

    Open questions at the time
    • Direct versus indirect PfCRT interaction unresolved
    • Mechanism by which PfHsp90 influences PfCRT function unknown
  7. 2021 Medium

    The transcriptional context of PfHsp90 was defined at both ends—how its own gene is induced by heat and how it in turn controls chromatin at febrile temperatures.

    Evidence Conditional knockout/ChIP showing PfAP2-HS activates hsp90 transcription at febrile temperatures, and ChIP plus inhibitor assays showing PfHsp90 represses PfSIR2A/B by recruiting H3K9me3 in P. falciparum 3D7

    PMID:33538363 PMID:34400833

    Open questions at the time
    • How a cytosolic chaperone accesses promoters and directs H3K9me3 mechanistically unclear
    • Whether repression is direct or via chaperoned nuclear factors unknown
  8. 2022 Medium

    The chromatin-regulatory role was refined to a direct chaperone-client relationship with a sirtuin deacetylase governing antigenic variation.

    Evidence Co-IP and inhibitor treatment (17-AAG, Radicicol) showing PfHsp90 stabilizes PfSir2A protein and HDAC activity, with var-gene derepression on inhibition in P. falciparum 3D7

    PMID:36121150

    Open questions at the time
    • Structural basis of PfHsp90-PfSir2A recognition undefined
    • Contribution relative to other var-silencing pathways unquantified
  9. 2024 High

    Unbiased proteome profiling identified the proteasome as a direct functional client, extending PfHsp90 beyond classical folding into proteostasis control.

    Evidence Thermal proteome profiling after PfHsp90 inhibition plus biochemical proteasome-activity assays using selective inhibitors in P. falciparum

    PMID:38492573

    Open questions at the time
    • Which proteasome subunits PfHsp90 engages directly not resolved
    • Stoichiometry and dynamics of the chaperone-proteasome interaction unknown
  10. 2025 Medium

    Solution-structure and nucleotide-binding studies mapped the conformational and cryptic-site features that distinguish PfHsp90 and complicate inhibitor targeting.

    Evidence SAXS showing an open flexible homodimer with C-terminal-driven dimerization, limited proteolysis identifying a cryptic C-terminal ATP site, and conditional-knockdown/binding assays contrasting geldanamycin versus AUY-922 resistance (bioRxiv preprint for #25)

    PMID:32679196 PMID:40907219 PMID:41279590

    Open questions at the time
    • Physiological role of the cryptic C-terminal nucleotide site untested in vivo
    • Mechanism of AUY-922 resistance despite enhanced binding unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PfHsp90's diverse activities—cytosolic client folding, proteasome chaperoning, nuclear transcriptional repression, and gamete-surface fertilization function—are partitioned and regulated within a single essential chaperone remains unresolved.
  • No unified model linking cytosolic chaperone activity to its nuclear and surface roles
  • Full endogenous client repertoire not defined
  • Mechanism of gamete-surface targeting unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
PFAHA1 (CO-CHAPERONE, ATPASE STIMULATOR) [#10]PFAP2-HS (TRANSCRIPTIONAL ACTIVATOR OF HSP90) [#14]PFCN (CALCINEURIN) [#5]PFCRT (DIRECT OR INDIRECT) [#13]PFFKBP35 (IMMUNOPHILIN, MEEVD-BINDING) [#5, #8]PFHOP [#7, #21]PFHSP70 [#0, #3, #7]PFP23 / PFP23A / PFP23B (CO-CHAPERONE, ATPASE SUPPRESSOR) [#9, #24]PFPP5 (TPR-DOMAIN SER/THR PHOSPHATASE) [#4, #3]PFSIR2A (CHAPERONE CLIENT/STABILIZED) [#16]
Complex memberships
PfHsp90-26S proteasome functional association [#17]PfHsp90-PfHsp70 hetero-oligomeric (~300 kDa, 11S) chaperone complex [#0]PfHsp90-PfHsp70-PfHop complex [#7]PfHsp90-PfHsp70-PfPP5-tubulin heat-shock multi-chaperone complex [#3]

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 PfHsp90 (PF3D7_0308500) exists in ~300 kDa, 11S hetero-oligomeric complexes containing PfHsp70, as shown by sedimentation analysis and size exclusion chromatography. Geldanamycin (GA) inhibits PfHsp90 and arrests parasite transition from ring to trophozoite stage (LD50 0.2 µM), and selectively inhibits PfHsp90 phosphorylation in GA-treated cultures. Sedimentation analysis, size exclusion chromatography, homology modeling of GA-binding pocket, flow cytometry for stage analysis, metabolic labeling The Journal of biological chemistry High 12584193
2010 Full-length recombinant PfHsp90 has the highest ATPase activity of all known Hsp90s (6-fold higher than human Hsp90); GA inhibits this ATPase activity more robustly than it inhibits human Hsp90. Mass spectrometry identified an acetylation site on PfHsp90 that overlaps with the Aha1 and p23 binding domain, and treatment with a histone deacetylase inhibitor caused partial dissociation of the PfHsp90 complex. In vitro ATPase assay with recombinant full-length protein, mass spectrometry, histone deacetylase inhibitor treatment with complex analysis The Journal of biological chemistry High 20837488
2003 PfHsp90 binds ATP in vitro, and this binding is specifically inhibited by geldanamycin. PfHsp90 mRNA is mainly expressed in ring and trophozoite stages, while the protein is found in all asexual erythrocytic stages. Recombinant protein expression, ATP-binding assay, in vitro growth inhibition assay, Western blot for stage-specific expression Malaria journal Medium 14514358
2004 PfHsp90 forms a multi-chaperone complex containing PfHsp70, PfPP5, and tubulin during heat shock. Inhibition of this complex by geldanamycin disrupts the complex and inhibits temperature-dependent progression from ring to trophozoite stage. Heat shock-mediated growth promotion is dependent on the PfHsp90 multi-chaperone complex. Co-immunoprecipitation, geldanamycin inhibition, flow cytometry for stage analysis, heat-shock treatment The Journal of biological chemistry Medium 15339915
2001 PfPP5, a TPR-domain serine/threonine phosphatase, physically associates with PfHsp90 in vivo, as demonstrated by co-immunoprecipitation of native proteins from P. falciparum. Co-immunoprecipitation of native parasite proteins BMC microbiology Medium 11737864
2005 PfFKBP35 (an immunophilin with TPR domain) associates with PfHsp90 via its TPR domain in vivo. Geldanamycin and ascomycin inhibit P. falciparum growth synergistically, and parasitic calcineurin (PfCN) also associates with PfHsp90 in vivo; GA inhibits the PfCN-PfHsp90 association. Co-immunoprecipitation, domain-deletion analysis, synergy growth inhibition assay Molecular and biochemical parasitology Medium 15811524 15850699
2010 Crystal structure of the N-terminal ATP-binding domain of PfHsp90 (PF3D7_0308500) was solved in apo and ADP-bound states at 2.3 Å resolution. The structure shows high similarity to human Hsp90 and contains a principal drug-binding pocket that likely binds geldanamycin in an identical manner to human Hsp90. X-ray crystallography Proteins High 20635416
2011 PfHop co-localizes with PfHsp90 and PfHsp70 in trophozoite-stage parasites and is present in a complex with both chaperones, as shown by gel filtration and co-immunoprecipitation. Co-immunoprecipitation, gel filtration, immunofluorescence co-localization Cell stress & chaperones Medium 22005844
2009 The crystal structure of the PfFKBP35 TPR domain was solved, and surface plasmon resonance and NMR confirmed direct interaction between the PfFKBP35-TPR domain and the PfHsp90 C-terminal pentapeptide (MEEVD). Mutational analysis of positively charged clamp residues showed all were important for Hsp90 C-terminal peptide binding. X-ray crystallography, surface plasmon resonance, NMR, site-directed mutagenesis Protein science High 19691130
2010 Pfp23 (P. falciparum co-chaperone p23) physically interacts with PfHsp90 using purified recombinant proteins. Pfp23 suppresses the ATPase activity of PfHsp90 in vitro. Site-directed mutagenesis identified residues K91, H93, W94, and K96 in Pfp23 as crucial for binding PfHsp90. Recombinant protein interaction assay, ATPase assay, site-directed mutagenesis, homology modeling Cellular and molecular life sciences High 20140477
2011 PfAha1 interacts with PfHsp90 as demonstrated by split-ubiquitin assay (in vivo) and GST pull-down (in vitro). The interaction is dependent on MgCl2 and ATP, competed by Pfp23, and sensitive to high salt. Residue N108 in PfAha1 is essential for PfHsp90 interaction. PfAha1 stimulates PfHsp90 ATPase activity. Split-ubiquitin assay, GST pull-down, site-directed mutagenesis, ATPase assay, bio-computational modelling The international journal of biochemistry & cell biology High 22100910
2012 Harmine specifically inhibits PfHsp90 ATP-binding domain with a KD of 40 µM (surface plasmon resonance). Site-directed mutagenesis revealed Arg98 in PfHsp90 is essential for harmine selectivity over human Hsp90. Surface plasmon resonance, site-directed mutagenesis, in vitro growth inhibition Antimicrobial agents and chemotherapy High 22615284
2014 Differences in the conformational dynamics of the ATP-binding pocket between PfHsp90 and human Hsp90 enable selective inhibitor binding. Novel 7-azaindole compounds bind exclusively to recombinant N-terminal domain of PfHsp90 but not to human Hsp90 or a PfHsp90 mutant engineered to have 'human-like' dynamics. Structure-based virtual screening, in vitro binding assay, yeast complementation system, mutagenesis Journal of medicinal chemistry High 24580531
2013 PfHsp90 interacts either directly or indirectly with the P. falciparum chloroquine resistance transporter (PfCRT), as identified by LC-MS/MS pulldown. Inhibition of PfHsp90 with PU-H71 synergizes with chloroquine against P. falciparum in vitro and in a P. berghei mouse model. LC-MS/MS interactome (pulldown), SPR binding assay, ATPase assay, flow cytometry, P. berghei mouse model PloS one Medium 24098696
2021 PfAP2-HS, an ApiAP2 transcription factor, activates transcription of hsp90 (PF3D7_0308500) at elevated (febrile) temperatures. Parasites lacking PfAP2-HS have reduced heat-shock survival and growth defects at 37°C. The main PfAP2-HS binding site in the genome coincides with a tandem G-box motif in the hsp70-1 promoter. Conditional knockdown/knockout, chromatin immunoprecipitation, transcriptomics, survival assays Nature microbiology High 34400833
2021 PfHsp90 acts as a transcriptional repressor of PfSIR2A and PfSIR2B at febrile temperatures. PfHsp90 is present at PfSIR2A and PfSIR2B promoter proximal regions, helps recruit H3K9me3 (heterochromatic mark), and its inhibition by 17-AAG or Radicicol reverses transcriptional downregulation of PfSIR2A/B. Chromatin immunoprecipitation (ChIP), inhibitor treatment (17-AAG, Radicicol), transcriptional reporter assays Molecular microbiology Medium 33538363
2022 PfHsp90 physically interacts with PfSir2A (demonstrated by co-immunoprecipitation), and inhibition of PfHsp90 by 17-AAG or Radicicol causes depletion of PfSir2A protein and abolishes its histone deacetylase activity, leading to derepression of var genes and ribosomal silencing. Co-immunoprecipitation, chemical inhibition (17-AAG, Radicicol), HDAC activity assay, var gene expression analysis mSphere Medium 36121150
2024 PfHsp90 directly promotes 26S proteasome function by chaperoning the active 26S complex. Thermal proteome profiling following PfHsp90 inhibition identified the proteasome as enriched among proteins with perturbed stability. Subsequent biochemical and cellular studies confirmed PfHsp90 promotes proteasome hydrolysis. Thermal proteome profiling, biochemical proteasome activity assays, cellular studies with selective PfHsp90 inhibitors (BX-2819, XL888, Tropane 1) Cell chemical biology High 38492573
2023 Hsp90 is present on the surface of Plasmodium female gametes and is a key determinant for fertilization. Anti-HSP90 antibodies binding to the female gamete surface inhibit fertilization. Phage peptide display screening, antibody binding assay, fertilization inhibition assay mBio Medium 38131664
2015 Class 2 imidazopyridazine compounds (non-pyrimidine linker) bind to the ATP-binding site in the N-terminal domain of PfHsp90 and inhibit parasite growth at the trophozoite stage, implicating PfHsp90 inhibition as their primary mechanism of action. Compound-pulldown/target identification, in vitro growth inhibition, parasite lines expressing modified kinases (gatekeeper mutants), stage-specific growth analysis Antimicrobial agents and chemotherapy Medium 26711771
2020 Violacein directly binds PfHsp90 (as well as PfHsp70-1), compromising chaperone activities in the parasite, leading to increased protein unfolding and proteasomal degradation and multi-stage growth inhibition. Chemical genomic profiling, direct binding assay (thermal shift/pull-down), ATPase assay, proteasome activity assay ACS infectious diseases Medium 33689276
2019 PfHop inhibits the ATPase activity of recombinant PfHsp90 while stimulating the ATPase activity of PfHsp70-1 in vitro. PfHop behaves primarily as an elongated dimer as characterized by small-angle X-ray scattering. In vitro ATPase assay, small-angle X-ray scattering, circular dichroism Biochimica et biophysica acta. Proteins and proteomics Medium 31525467
2020 Solution structure of full-length recombinant PfHsp90 characterized by small-angle X-ray scattering reveals an open, highly elongated and flexible homodimer. PfHsp90 interacts with adenosine nucleotides via the N-terminal domain; Mg2+ is critical for strong nucleotide binding. The C-terminal domain is essential for dimerization. Small-angle X-ray scattering (SAXS), isothermal titration calorimetry/fluorescence-based nucleotide binding assays, domain-deletion constructs Archives of biochemistry and biophysics Medium 32679196
2025 A cryptic C-terminal binding site on PfHsp90 interacts specifically with ATP; limited proteolysis experiments suggest association with ATP, dATP, and ADP but not AMP or GTP. Mutagenesis studies were used to interrogate the molecular basis of this interaction. Affinity experiments with lysine-reactive nucleotide analog and ATP resin, limited proteolysis, site-directed mutagenesis, in silico analysis Bioorganic & medicinal chemistry Medium 40907219
2017 Two p23 co-chaperones (Pfp23A and Pfp23B) are present in P. falciparum and both inhibit the ATPase activity of recombinant PfHsp90 in vitro, validating them as functional Hsp90 co-chaperones. Pfp23A is more structurally stable than Pfp23B. Recombinant protein expression, in vitro ATPase assay, thermal stability assay, small-angle X-ray scattering International journal of biological macromolecules Medium 29191421
2025 Two HSP90 inhibitors (geldanamycin and AUY-922) targeting the identical ATP-binding site of PfHsp90 show dramatically different resistance profiles in P. falciparum. Conditional HSP90 knockdown increases geldanamycin sensitivity but leaves AUY-922 activity unaffected, suggesting AUY-922 may engage multiple Hsp90 family members. The A41S mutation in the ATP-binding site enhances AUY-922 binding affinity yet correlates with resistance. Drug resistance selection, yeast complementation, conditional knockdown, in vitro binding assays, in silico analysis bioRxivpreprint Medium 41279590

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Heat shock protein 90 function is essential for Plasmodium falciparum growth in human erythrocytes. The Journal of biological chemistry 189 12584193
2010 Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug. The Journal of biological chemistry 139 20837488
2007 Chaperoning a cellular upheaval in malaria: heat shock proteins in Plasmodium falciparum. Molecular and biochemical parasitology 110 17307260
2012 Charged linker sequence modulates eukaryotic heat shock protein 90 (Hsp90) chaperone activity. Proceedings of the National Academy of Sciences of the United States of America 105 22315411
2007 Systems analysis of chaperone networks in the malarial parasite Plasmodium falciparum. PLoS computational biology 94 17941702
2011 Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis. Protein and peptide letters 90 20955165
2009 Plasmodial heat shock proteins: targets for chemotherapy. FEMS immunology and medical microbiology 85 20041948
2003 The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin. Malaria journal 82 14514358
2001 Host chaperones are recruited in membrane-bound complexes by Plasmodium falciparum. The Journal of biological chemistry 80 11711553
2004 Recurrent fever promotes Plasmodium falciparum development in human erythrocytes. The Journal of biological chemistry 70 15339915
2010 A repurposing strategy identifies novel synergistic inhibitors of Plasmodium falciparum heat shock protein 90. Journal of medicinal chemistry 64 20349996
2011 Characterisation of the Plasmodium falciparum Hsp70-Hsp90 organising protein (PfHop). Cell stress & chaperones 58 22005844
2005 The FK506-binding protein of the malaria parasite, Plasmodium falciparum, is a FK506-sensitive chaperone with FK506-independent calcineurin-inhibitory activity. Molecular and biochemical parasitology 56 15850699
1994 Molecular characterization of the heat shock protein 90 gene of the human malaria parasite Plasmodium falciparum. Molecular and biochemical parasitology 56 7838176
2012 Harmine is a potent antimalarial targeting Hsp90 and synergizes with chloroquine and artemisinin. Antimicrobial agents and chemotherapy 52 22615284
2010 Structure of the ATP-binding domain of Plasmodium falciparum Hsp90. Proteins 52 20635416
2005 Plasmodium falciparum calcineurin and its association with heat shock protein 90: mechanisms for the antimalarial activity of cyclosporin A and synergism with geldanamycin. Molecular and biochemical parasitology 51 15811524
2015 Imidazopyridazine Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 Also Target Cyclic GMP-Dependent Protein Kinase and Heat Shock Protein 90 To Kill the Parasite at Different Stages of Intracellular Development. Antimicrobial agents and chemotherapy 47 26711771
2021 A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures. Nature microbiology 45 34400833
2010 Malaria heat shock proteins: drug targets that chaperone other drug targets. Infectious disorders drug targets 44 20334623
2014 Differences in conformational dynamics between Plasmodium falciparum and human Hsp90 orthologues enable the structure-based discovery of pathogen-selective inhibitors. Journal of medicinal chemistry 42 24580531
2009 The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities. Molecular and biochemical parasitology 40 19320098
2018 Structural and biochemical characterization of Plasmodium falciparum Hsp70-x reveals functional versatility of its C-terminal EEVN motif. Proteins 38 30183110
2017 Polymyxin B inhibits the chaperone activity of Plasmodium falciparum Hsp70. Cell stress & chaperones 38 28455613
2015 Plasmodium falciparum Hop (PfHop) Interacts with the Hsp70 Chaperone in a Nucleotide-Dependent Fashion and Exhibits Ligand Selectivity. PloS one 38 26267894
1994 Sequence, transcript characterization and polymorphisms of a Plasmodium falciparum gene belonging to the heat-shock protein (HSP) 90 family. Gene 38 7828879
2016 Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles. Journal of medicinal chemistry 35 27312008
2010 Chaperone expression profiles correlate with distinct physiological states of Plasmodium falciparum in malaria patients. Malaria journal 35 20719001
2001 A novel tetratricopeptide repeat (TPR) containing PP5 serine/threonine protein phosphatase in the malaria parasite, Plasmodium falciparum. BMC microbiology 35 11737864
2018 Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity. Antimicrobial agents and chemotherapy 34 29339390
2017 (-)-Epigallocatechin-3-Gallate Inhibits the Chaperone Activity of Plasmodium falciparum Hsp70 Chaperones and Abrogates Their Association with Functional Partners. Molecules (Basel, Switzerland) 34 29206141
2013 A purine analog synergizes with chloroquine (CQ) by targeting Plasmodium falciparum Hsp90 (PfHsp90). PloS one 34 24098696
2016 In vitro and in vivo anti-malarial activity of novel harmine-analog heat shock protein 90 inhibitors: a possible partner for artemisinin. Malaria journal 33 27903279
2007 Three-dimensional structure of heat shock protein 90 from Plasmodium falciparum: molecular modelling approach to rational drug design against malaria. Journal of biosciences 32 17536172
2013 Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance. Pathogens (Basel, Switzerland) 30 25436880
2019 Harmicines - harmine and cinnamic acid hybrids as novel antiplasmodial hits. European journal of medicinal chemistry 28 31812035
2022 Design and synthesis of harmiquins, harmine and chloroquine hybrids as potent antiplasmodial agents. European journal of medicinal chemistry 26 35551033
2021 General Structural and Functional Features of Molecular Chaperones. Advances in experimental medicine and biology 26 34569020
2017 Identification and characterization of the antiplasmodial activity of Hsp90 inhibitors. Malaria journal 26 28724415
1994 Immunogenicity and antigenicity of a Plasmodium falciparum protein fraction (90-110 kDa) able to protect squirrel monkeys against asexual blood stages. Vaccine 26 8303938
2012 Anti-malarial activity of geldanamycin derivatives in mice infected with Plasmodium yoelii. Malaria journal 24 22361388
2013 Heat shock protein 90 inhibitors as broad spectrum anti-infectives. Current pharmaceutical design 23 22920905
2009 Crystallographic structure of the tetratricopeptide repeat domain of Plasmodium falciparum FKBP35 and its molecular interaction with Hsp90 C-terminal pentapeptide. Protein science : a publication of the Protein Society 23 19691130
2013 A review of recent patents on the protozoan parasite HSP90 as a drug target. Recent patents on biotechnology 21 23002958
2001 Antibodies specific for heat shock proteins in human and murine malaria. Microbes and infection 21 11369272
2021 Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future. Cells 18 34831072
2011 Target highlights in CASP9: Experimental target structures for the critical assessment of techniques for protein structure prediction. Proteins 17 22020785
2010 Characterization of Plasmodium falciparum co-chaperone p23: its intrinsic chaperone activity and interaction with Hsp90. Cellular and molecular life sciences : CMLS 17 20140477
2022 Hsp90 and Associated Co-Chaperones of the Malaria Parasite. Biomolecules 16 35892329
2019 Structural studies of the Hsp70/Hsp90 organizing protein of Plasmodium falciparum and its modulation of Hsp70 and Hsp90 ATPase activities. Biochimica et biophysica acta. Proteins and proteomics 16 31525467
2019 Plasmodium falciparum R2TP complex: driver of parasite Hsp90 function. Biophysical reviews 16 31734827
2014 Co-chaperones of Hsp90 in Plasmodium falciparum and their concerted roles in cellular regulation. Parasitology 16 24560171
2024 Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome. Cell chemical biology 15 38492573
2023 Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Hsp90. ACS omega 15 37867657
2021 Further investigation of harmicines as novel antiplasmodial agents: Synthesis, structure-activity relationship and insight into the mechanism of action. European journal of medicinal chemistry 15 34274829
2021 Plasmodium berghei Hsp90 contains a natural immunogenic I-Ab-restricted antigen common to rodent and human Plasmodium species. Current research in immunology 15 35492393
2018 Novobiocin-ferrocene conjugates possessing anticancer and antiplasmodial activity independent of HSP90 inhibition. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 15 30542925
2018 In silico identification and evaluation of potential interaction of Azadirachta indica phytochemicals with Plasmodium falciparum heat shock protein 90. Journal of molecular graphics & modelling 15 30544005
2020 Biophysical analysis of Plasmodium falciparum Hsp70-Hsp90 organising protein (PfHop) reveals a monomer that is characterised by folded segments connected by flexible linkers. PloS one 14 32343703
2020 Novel Harmicines with Improved Potency against Plasmodium. Molecules (Basel, Switzerland) 14 32977642
2022 Inhibition of Plasmodium falciparum Hsp70-Hop partnership by 2-phenylthynesulfonamide. Frontiers in molecular biosciences 13 36177352
2019 Thermodynamic analysis of interactions of the Hsp90 with adenosine nucleotides: A comparative perspective. International journal of biological macromolecules 13 30797004
2020 Solution structure of Plasmodium falciparum Hsp90 indicates a high flexible dimer. Archives of biochemistry and biophysics 12 32679196
2014 Exploring in vitro and in vivo Hsp90 inhibitors activity against human protozoan parasites. Bioorganic & medicinal chemistry letters 12 25547934
2024 Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds. Bioorganic & medicinal chemistry 11 38677112
2023 The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery. Frontiers in molecular biosciences 11 37457831
2021 Identification of Plasmodium falciparum heat shock 90 inhibitors via molecular docking. Bioorganic & medicinal chemistry letters 11 33513390
2017 Comparative studies of the low-resolution structure of two p23 co-chaperones for Hsp90 identified in Plasmodium falciparum genome. International journal of biological macromolecules 11 29191421
2014 Plasmodium falciparum Hop: detailed analysis on complex formation with Hsp70 and Hsp90. Biochemical and biophysical research communications 11 25482441
2013 Targeting heat shock protein 90 for malaria. Mini reviews in medicinal chemistry 11 24070209
2011 Molecular analysis of Plasmodium falciparum co-chaperone Aha1 supports its interaction with and regulation of Hsp90 in the malaria parasite. The international journal of biochemistry & cell biology 11 22100910
2023 Plasmodium-Resistant Indole Diterpenoid Biosynthesis Gene Cluster Derived from Aspergillus oryzae Was Activated by Exogenous P450 Gene Ast B. Journal of natural products 10 37257055
2021 Febrile temperature causes transcriptional downregulation of Plasmodium falciparum Sirtuins through Hsp90-dependent epigenetic modification. Molecular microbiology 10 33538363
2021 Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity. ACS infectious diseases 9 33689276
2018 Model System Identifies Kinetic Driver of Hsp90 Inhibitor Activity against African Trypanosomes and Plasmodium falciparum. Antimicrobial agents and chemotherapy 9 29866861
2025 Two sides of the same coin: heat shock proteins as biomarkers and therapeutic targets for some complex diseases. Frontiers in molecular biosciences 8 40051500
2024 In silico screening of selective ATP mimicking inhibitors targeting the Plasmodium falciparum Grp94. Journal of biomolecular structure & dynamics 7 38498364
2024 Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update. Cell stress & chaperones 7 38518861
2024 Characterization and Inhibition of the Chaperone Function of Plasmodium falciparum Glucose-Regulated Protein 94 kDa (Pf Grp94). Proteins 7 39670568
2024 Ursolic acid acetate and iso-mukaadial acetate bind to Plasmodium falciparum Hsp90, abrogating its chaperone function in vitro. Naunyn-Schmiedeberg's archives of pharmacology 5 38252299
2023 Plasmodium female gamete surface HSP90 is a key determinant for fertilization. mBio 5 38131664
2022 Heat Shock Protein 90 Regulates the Activity of Histone Deacetylase Sir2 in Plasmodium falciparum. mSphere 5 36121150
2024 Auto QSAR-based active learning docking for hit identification of potential inhibitors of Plasmodium falciparum Hsp90 as antimalarial agents. PloS one 4 39585817
2025 Hsp90 and associates shaping parasite biology. mSphere 3 40990539
2025 Plasmodium knowlesi Heat Shock Protein 90s: In Silico Analysis Reveals Unique Druggable Structural Features. International journal of molecular sciences 1 41465491
2025 The possibilities and challenges associated with selective targeting Plasmodium falciparum Hsp90 for Malaria. Transactions of the Royal Society of South Africa. Royal Society of South Africa 1 41836916
2024 Study of the naturally occurring lignan brachangobinan A as antiplasmodial agent: Synthesis, biological evaluation, and in silico prediction. Chemico-biological interactions 1 39710055
2022 Analysis of Plasmodium falciparum myosin B ATPase activity and structure in complex with the calmodulin-like domain of its light chain MLC-B. The Journal of biological chemistry 1 36273584
2026 Synthetic quinolone-tethered aminoguanidine derivatives exhibit potent anti-plasmodial activity. International journal of antimicrobial agents 0 41921671
2026 Heat shock protein Gp96 (Grp94) in malaria: functional insights at the host-parasite interface and therapeutic perspectives. Frontiers in cell and developmental biology 0 41970953
2025 Investigation of a cryptic ligand binding site on Plasmodium falciparum Hsp90. Bioorganic & medicinal chemistry 0 40907219
2025 Shared Binding Site but Divergent Resistance Profiles Uncover Novel Resistance Mechanisms in Plasmodium HSP90 Inhibitors. bioRxiv : the preprint server for biology 0 41279590