+Open data
-Basic information
Entry | Database: PDB / ID: 7kw7 | ||||||
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Title | Atomic cryoEM structure of Hsp90-Hsp70-Hop-GR | ||||||
Components |
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Keywords | CHAPERONE / 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 / death receptor agonist activity / Viral RNP Complexes in the Host Cell Nucleus / C3HC4-type RING finger domain binding ...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 / death receptor agonist activity / Viral RNP Complexes in the Host Cell Nucleus / C3HC4-type RING finger domain binding / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / steroid hormone binding / positive regulation of microtubule nucleation / PTK6 Expression / ATP-dependent protein disaggregase activity / dynein axonemal particle / neuroinflammatory response / glucocorticoid metabolic process / misfolded protein binding / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / microglia differentiation / mammary gland duct morphogenesis / positive regulation of tumor necrosis factor-mediated signaling pathway / regulation of mitotic spindle assembly / maternal behavior / astrocyte differentiation / cellular response to interleukin-7 / lysosomal transport / cellular response to glucocorticoid stimulus / transcription regulator inhibitor activity / protein folding chaperone complex / aggresome / RND1 GTPase cycle / motor behavior / positive regulation of tau-protein kinase activity / 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 / protein insertion into mitochondrial outer membrane / adrenal gland development / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / regulation of gluconeogenesis / cellular response to steroid hormone stimulus / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / 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 / Assembly and release of respiratory syncytial virus (RSV) virions / dendritic growth cone / mRNA catabolic process / regulation of postsynaptic membrane neurotransmitter receptor levels / Sema3A PAK dependent Axon repulsion / chaperone cofactor-dependent protein refolding / regulation of protein ubiquitination / skeletal muscle contraction / protein unfolding / telomere maintenance via telomerase / HSF1-dependent transactivation / response to unfolded protein / positive regulation of cell size / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / chaperone-mediated protein complex assembly / cellular response to unfolded protein / regulation of protein-containing complex assembly / HSF1 activation / Regulation of HSF1-mediated heat shock response / Attenuation phase / estrogen response element binding / RHOBTB2 GTPase cycle / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of defense response to virus by host / eNOS activation / axonal growth cone / positive regulation of lamellipodium assembly / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / nuclear receptor-mediated steroid hormone signaling pathway / DNA polymerase binding / core promoter sequence-specific DNA binding / activation of innate immune response / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.57 Å | ||||||
Authors | Wang, R.Y. / Noddings, C.M. / Kirschke, E. / Myasnikov, A. / Johnson, J.L. / Agard, D.A. | ||||||
Funding support | United States, 1items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7kw7.cif.gz | 1018.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7kw7.ent.gz | 838.1 KB | Display | PDB format |
PDBx/mmJSON format | 7kw7.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7kw7_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 7kw7_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 7kw7_validation.xml.gz | 80.6 KB | Display | |
Data in CIF | 7kw7_validation.cif.gz | 125.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/kw/7kw7 ftp://data.pdbj.org/pub/pdb/validation_reports/kw/7kw7 | HTTPS FTP |
-Related structure data
Related structure data | 23050MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 4 types, 6 molecules ABCDEF
#1: Protein | 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 | 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 | | 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 | | 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 | #6: Chemical | #7: Chemical | |
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-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE-PROPANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 80 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||
3D reconstruction | Resolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85619 / Symmetry type: POINT | ||||||||||||||||||||
Atomic model building | B value: 80 / Protocol: FLEXIBLE FIT / Space: REAL |