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- PDB-7l7i: Cryo-EM structure of Hsp90:FKBP51:p23 closed-state complex -

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Basic information

Entry
Database: PDB / ID: 7l7i
TitleCryo-EM structure of Hsp90:FKBP51:p23 closed-state complex
Components
  • Heat shock protein HSP 90-alpha
  • Peptidyl-prolyl cis-trans isomerase FKBP5
  • Prostaglandin E synthase 3
KeywordsISOMERASE/CHAPERONE / ISOMERASE-CHAPERONE complex
Function / homology
Function and homology information


lung saccule development / prostaglandin-E synthase / prostaglandin-E synthase activity / nuclear receptor-mediated glucocorticoid signaling pathway / prostanoid biosynthetic process / Aryl hydrocarbon receptor signalling / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / glycogen biosynthetic process / telomerase holoenzyme complex / response to alcohol ...lung saccule development / prostaglandin-E synthase / prostaglandin-E synthase activity / nuclear receptor-mediated glucocorticoid signaling pathway / prostanoid biosynthetic process / Aryl hydrocarbon receptor signalling / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / glycogen biosynthetic process / telomerase holoenzyme complex / response to alcohol / Modulation of host responses by IFN-stimulated genes / protein folding chaperone complex / prostaglandin biosynthetic process / sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / skin development / sperm plasma membrane / chaperone-mediated autophagy / FK506 binding / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / mitochondrial transport / Uptake and function of diphtheria toxin / protein insertion into mitochondrial outer membrane / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / dendritic growth cone / : / Sema3A PAK dependent Axon repulsion / protein unfolding / positive regulation of cell size / regulation of protein ubiquitination / HSF1-dependent transactivation / response to unfolded protein / enzyme-substrate adaptor activity / skeletal muscle contraction / regulation of postsynaptic membrane neurotransmitter receptor levels / regulation of protein-containing complex assembly / HSF1 activation / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / axonal growth cone / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / MECP2 regulates neuronal receptors and channels / eNOS activation / nitric oxide metabolic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / : / DNA polymerase binding / heat shock protein binding / positive regulation of defense response to virus by host / response to salt stress / Signaling by ERBB2 / cardiac muscle cell apoptotic process / positive regulation of telomere maintenance via telomerase / endocytic vesicle lumen / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / nitric-oxide synthase regulator activity / Recruitment of mitotic centrosome proteins and complexes / telomere maintenance / Recruitment of NuMA to mitotic centrosomes / activation of innate immune response / Anchoring of the basal body to the plasma membrane / lysosomal lumen / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / response to cold / ESR-mediated signaling / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / peptidyl-prolyl cis-trans isomerase activity / AURKA Activation by TPX2 / VEGFR2 mediated vascular permeability / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 isomerase activity / peptidylprolyl isomerase
Similarity search - Function
Co-chaperone protein p23-like / CS domain / CS domain / CS domain profile. / : / HSP20-like chaperone / Chitinase A; domain 3 - #40 / Tetratricopeptide repeat / Tetratricopeptide repeat domain / Chitinase A; domain 3 ...Co-chaperone protein p23-like / CS domain / CS domain / CS domain profile. / : / HSP20-like chaperone / Chitinase A; domain 3 - #40 / Tetratricopeptide repeat / Tetratricopeptide repeat domain / Chitinase A; domain 3 / Tetratricopeptide repeat / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Peptidyl-prolyl cis-trans isomerase domain superfamily / TPR repeat region circular profile. / TPR repeat profile. / Tetratricopeptide repeats / Tetratricopeptide repeat / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat / Alpha Horseshoe / Tetratricopeptide-like helical domain superfamily / Ribosomal protein S5 domain 2-type fold / Roll / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Heat shock protein HSP 90-alpha / Peptidyl-prolyl cis-trans isomerase FKBP5 / Prostaglandin E synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLee, K. / Thwin, A.C. / Tse, E. / Gates, S.N. / Southworth, D.R.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG002132 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG068125 United States
CitationJournal: Mol Cell / Year: 2021
Title: The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state.
Authors: Kanghyun Lee / Aye C Thwin / Cory M Nadel / Eric Tse / Stephanie N Gates / Jason E Gestwicki / Daniel R Southworth /
Abstract: The Hsp90 chaperone promotes folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 ...The Hsp90 chaperone promotes folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 immunophilin binds Hsp90 with its tetratricopeptide repeat (TPR) domain and catalyzes peptidyl-prolyl isomerase (PPIase) activity during folding of kinases, nuclear receptors, and tau. Here we determined the cryoelectron microscopy (cryo-EM) structure of the human Hsp90:FKBP51:p23 complex to 3.3 Å, which, together with mutagenesis and crosslinking analyses, reveals the basis for cochaperone binding to Hsp90 during client maturation. A helix extension in the TPR functions as a key recognition element, interacting across the Hsp90 C-terminal dimer interface presented in the closed, ATP conformation. The PPIase domain is positioned along the middle domain, adjacent to Hsp90 client binding sites, whereas a single p23 makes stabilizing interactions with the N-terminal dimer. With this architecture, FKBP51 is positioned to act on specific client residues presented during Hsp90-catalyzed remodeling.
History
DepositionDec 28, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 25, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 15, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.2May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Assembly

Deposited unit
C: Peptidyl-prolyl cis-trans isomerase FKBP5
A: Heat shock protein HSP 90-alpha
B: Heat shock protein HSP 90-alpha
E: Prostaglandin E synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)240,5866
Polymers239,5744
Non-polymers1,0122
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Peptidyl-prolyl cis-trans isomerase FKBP5 / PPIase FKBP5 / 51 kDa FK506-binding protein / FKBP-51 / 54 kDa progesterone receptor-associated ...PPIase FKBP5 / 51 kDa FK506-binding protein / FKBP-51 / 54 kDa progesterone receptor-associated immunophilin / Androgen-regulated protein 6 / FF1 antigen / FK506-binding protein 5 / FKBP-5 / FKBP54 / p54 / HSP90-binding immunophilin / Rotamase


Mass: 51290.191 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP5, AIG6, FKBP51 / Production host: Escherichia coli (E. coli) / References: UniProt: Q13451, peptidylprolyl isomerase
#2: Protein Heat shock protein HSP 90-alpha / Heat shock 86 kDa / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / ...Heat shock 86 kDa / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / Renal carcinoma antigen NY-REN-38


Mass: 84781.727 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Escherichia coli (E. coli) / References: UniProt: P07900
#3: Protein Prostaglandin E synthase 3 / Cytosolic prostaglandin E2 synthase / cPGES / Hsp90 co-chaperone / Progesterone receptor complex ...Cytosolic prostaglandin E2 synthase / cPGES / Hsp90 co-chaperone / Progesterone receptor complex p23 / Telomerase-binding protein p23


Mass: 18720.395 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTGES3, P23, TEBP / Production host: Escherichia coli (E. coli) / References: UniProt: Q15185, prostaglandin-E synthase
#4: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Hsp90:FKBP51:p23 closed-state complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recording
IDImaging-IDElectron dose (e/Å2)Film or detector model
1170GATAN K2 SUMMIT (4k x 4k)
2166GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
4cryoSPARC2CTF correction
13cryoSPARC23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 576169
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 121882 / Symmetry type: POINT

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