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- PDB-7kw7: Atomic cryoEM structure of Hsp90-Hsp70-Hop-GR -

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Basic information

Entry
Database: PDB / ID: 7kw7
TitleAtomic cryoEM structure of Hsp90-Hsp70-Hop-GR
Components
  • Glucocorticoid receptor
  • Heat shock 70 kDa protein 1A
  • Heat shock protein HSP 90-alphaHeat shock response
  • Stress-induced-phosphoprotein 1
KeywordsCHAPERONE / Client-loading
Function / homology
Function and homology information


positive regulation of endoribonuclease activity / denatured protein binding / Regulation of NPAS4 gene transcription / cellular heat acclimation / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / negative regulation of inclusion body assembly / Viral RNP Complexes in the Host Cell Nucleus / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / death receptor agonist activity ...positive regulation of endoribonuclease activity / denatured protein binding / Regulation of NPAS4 gene transcription / cellular heat acclimation / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / negative regulation of inclusion body assembly / Viral RNP Complexes in the Host Cell Nucleus / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / death receptor agonist activity / C3HC4-type RING finger domain binding / dynein axonemal particle / steroid hormone binding / PTK6 Expression / ATP-dependent protein disaggregase activity / positive regulation of microtubule nucleation / neuroinflammatory response / glucocorticoid metabolic process / microglia differentiation / maternal behavior / mammary gland duct morphogenesis / nucleus localization / misfolded protein binding / regulation of mitotic spindle assembly / positive regulation of tumor necrosis factor-mediated signaling pathway / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / astrocyte differentiation / cellular response to interleukin-7 / protein folding chaperone complex / transcription regulator inhibitor activity / cellular response to glucocorticoid stimulus / aggresome / RND1 GTPase cycle / motor behavior / lysosomal transport / sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / positive regulation of tau-protein kinase activity / protein insertion into mitochondrial outer membrane / regulation of gluconeogenesis / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / adrenal gland development / Rho GDP-dissociation inhibitor binding / cellular response to steroid hormone stimulus / Uptake and function of diphtheria toxin / mitochondrial transport / 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 / PIWI-interacting RNA (piRNA) biogenesis / TPR domain binding / non-chaperonin molecular chaperone ATPase / regulation of postsynaptic membrane neurotransmitter receptor levels / mRNA catabolic process / dendritic growth cone / chaperone cofactor-dependent protein refolding / Sema3A PAK dependent Axon repulsion / skeletal muscle contraction / regulation of protein ubiquitination / positive regulation of cell size / protein unfolding / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / HSF1 activation / Regulation of HSF1-mediated heat shock response / chaperone-mediated protein complex assembly / regulation of protein-containing complex assembly / Attenuation phase / cellular response to unfolded protein / estrogen response element binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / eNOS activation / DNA polymerase binding / axonal growth cone / intracellular steroid hormone receptor signaling pathway / ATP metabolic process / inclusion body / protein folding chaperone / core promoter sequence-specific DNA binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
Similarity search - Function
STI1/HOP, DP domain / STI1/HOP, DP domain / Tetratricopeptide repeat 2 / Tetratricopeptide repeat / Glucocorticoid receptor / Glucocorticoid receptor / Heat shock chaperonin-binding / Heat shock chaperonin-binding motif. / TPR repeat / Tetratricopeptide repeat ...STI1/HOP, DP domain / STI1/HOP, DP domain / Tetratricopeptide repeat 2 / Tetratricopeptide repeat / Glucocorticoid receptor / Glucocorticoid receptor / Heat shock chaperonin-binding / Heat shock chaperonin-binding motif. / TPR repeat / Tetratricopeptide repeat / Heat shock hsp70 proteins family signature 2. / Heat shock hsp70 proteins family signature 1. / Heat shock hsp70 proteins family signature 3. / Heat shock protein 70, conserved site / Heat shock protein 70kD, peptide-binding domain superfamily / Heat shock protein 70 family / Hsp70 protein / Heat shock protein 70kD, C-terminal domain superfamily / 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 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / 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 / ATPase, nucleotide binding domain / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type / Tetratricopeptide-like helical domain superfamily / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / : / Glucocorticoid receptor / Heat shock protein HSP 90-alpha / Heat shock 70 kDa protein 1A / Stress-induced-phosphoprotein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.57 Å
AuthorsWang, R.Y. / Noddings, C.M. / Kirschke, E. / Myasnikov, A. / Johnson, J.L. / Agard, D.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nature / Year: 2022
Title: Structure of Hsp90-Hsp70-Hop-GR reveals the Hsp90 client-loading mechanism.
Authors: Ray Yu-Ruei Wang / Chari M Noddings / Elaine Kirschke / Alexander G Myasnikov / Jill L Johnson / David A Agard /
Abstract: Maintaining a healthy proteome is fundamental for the survival of all organisms. Integral to this are Hsp90 and Hsp70, molecular chaperones that together facilitate the folding, remodelling and ...Maintaining a healthy proteome is fundamental for the survival of all organisms. Integral to this are Hsp90 and Hsp70, molecular chaperones that together facilitate the folding, remodelling and maturation of the many 'client proteins' of Hsp90. The glucocorticoid receptor (GR) is a model client protein that is strictly dependent on Hsp90 and Hsp70 for activity. Chaperoning GR involves a cycle of inactivation by Hsp70; formation of an inactive GR-Hsp90-Hsp70-Hop 'loading' complex; conversion to an active GR-Hsp90-p23 'maturation' complex; and subsequent GR release. However, to our knowledge, a molecular understanding of this intricate chaperone cycle is lacking for any client protein. Here we report the cryo-electron microscopy structure of the GR-loading complex, in which Hsp70 loads GR onto Hsp90, uncovering the molecular basis of direct coordination by Hsp90 and Hsp70. The structure reveals two Hsp70 proteins, one of which delivers GR and the other scaffolds the Hop cochaperone. Hop interacts with all components of the complex, including GR, and poises Hsp90 for subsequent ATP hydrolysis. GR is partially unfolded and recognized through an extended binding pocket composed of Hsp90, Hsp70 and Hop, revealing the mechanism of GR loading and inactivation. Together with the GR-maturation complex structure, we present a complete molecular mechanism of chaperone-dependent client remodelling, and establish general principles of client recognition, inhibition, transfer and activation.
History
DepositionNov 30, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 26, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Feb 2, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

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  • Deposited structure unit
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Assembly

Deposited unit
A: Heat shock protein HSP 90-alpha
B: Heat shock protein HSP 90-alpha
C: Heat shock 70 kDa protein 1A
D: Heat shock 70 kDa protein 1A
E: Stress-induced-phosphoprotein 1
F: Glucocorticoid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)459,23712
Polymers458,2566
Non-polymers9816
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area21090 Å2
ΔGint-115 kcal/mol
Surface area117770 Å2

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Components

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Protein , 4 types, 6 molecules ABCDEF

#1: Protein Heat shock protein HSP 90-alpha / Heat shock response / 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
#2: Protein Heat shock 70 kDa protein 1A / Heat shock 70 kDa protein 1 / HSP70.1


Mass: 70140.133 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSPA1A, HSP72, HSPA1, HSX70 / Production host: unidentified baculovirus / References: UniProt: P0DMV8
#3: Protein Stress-induced-phosphoprotein 1 / STI1 / Hsc70/Hsp90-organizing protein / Hop / Renal carcinoma antigen NY-REN-11 / Transformation- ...STI1 / Hsc70/Hsp90-organizing protein / Hop / Renal carcinoma antigen NY-REN-11 / Transformation-sensitive protein IEF SSP 3521


Mass: 62738.301 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STIP1 / Production host: Escherichia coli (E. coli) / References: UniProt: P31948
#4: Protein Glucocorticoid receptor / / GR / Nuclear receptor subfamily 3 group C member 1


Mass: 85673.906 Da / Num. of mol.: 1 / Mutation: F602S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NR3C1, GRL / Production host: Escherichia coli (E. coli) / References: UniProt: P04150

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Non-polymers , 3 types, 6 molecules

#5: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE / Adenosine diphosphate


Mass: 427.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#7: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K

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Details

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

Component
IDNameTypeEntity IDParent-IDSource
1Hsp90-Hsp70-Hop-GR complexCOMPLEX#1-#40MULTIPLE SOURCES
2Heat shock protein HSP 90-alphaHeat shock responseCOMPLEX#11RECOMBINANT
3Heat shock 70 kDa protein 1ACOMPLEX#21RECOMBINANT
4Stress-induced-phosphoprotein 1COMPLEX#31RECOMBINANT
5Glucocorticoid receptorCOMPLEX#41RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Homo sapiens (human)9606
55Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Escherichia coli (E. coli)562
33unidentified baculovirus10469
44Escherichia coli (E. coli)562
55Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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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 FIELDBright-field microscopy
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
7Rosettamodel fitting
9RELION3initial Euler assignment
10RELION3final Euler assignment
13Rosettamodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85619 / Symmetry type: POINT
Atomic model buildingB value: 80 / Protocol: FLEXIBLE FIT / Space: REAL

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