+Open data
-Basic information
Entry | Database: PDB / ID: 8ffw | ||||||
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Title | Cryo-EM structure of the GR-Hsp90-FKBP51 complex | ||||||
Components |
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Keywords | CHAPERONE / steroid hormone receptor / ligand binding / ATP binding / protein folding | ||||||
Function / homology | Function and homology information Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / steroid hormone binding / PTK6 Expression / neuroinflammatory response / glucocorticoid metabolic process / microglia differentiation / mammary gland duct morphogenesis / maternal behavior ...Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / steroid hormone binding / PTK6 Expression / neuroinflammatory response / glucocorticoid metabolic process / microglia differentiation / mammary gland duct morphogenesis / maternal behavior / astrocyte differentiation / cellular response to glucocorticoid stimulus / 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 / FK506 binding / 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 / regulation of postsynaptic membrane neurotransmitter receptor levels / Sema3A PAK dependent Axon repulsion / 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 / chaperone-mediated protein complex assembly / regulation of protein-containing complex assembly / HSF1 activation / 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 / nuclear receptor-mediated steroid hormone signaling pathway / DNA polymerase binding / core promoter sequence-specific DNA binding / MECP2 regulates neuronal receptors and channels / activation of innate immune response / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / cellular response to transforming growth factor beta stimulus / chaperone-mediated protein folding / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Signaling by ERBB2 / heat shock protein binding / response to salt stress / cardiac muscle cell apoptotic process / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / positive regulation of cardiac muscle contraction / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / steroid binding / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / TBP-class protein binding / response to cold / protein tyrosine kinase binding / lysosomal lumen / AURKA Activation by TPX2 / Constitutive Signaling by Overexpressed ERBB2 / cellular response to dexamethasone stimulus / ESR-mediated signaling Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.23 Å | ||||||
Authors | Noddings, C.M. / Agard, D.A. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Struct Mol Biol / Year: 2023 Title: Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor. Authors: Chari M Noddings / Jill L Johnson / David A Agard / Abstract: Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins, including the glucocorticoid receptor (GR). Previously, we revealed that Hsp70 ...Hsp90 is an essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins, including the glucocorticoid receptor (GR). Previously, we revealed that Hsp70 and Hsp90 remodel the conformation of GR to regulate ligand binding, aided by co-chaperones. In vivo, the co-chaperones FKBP51 and FKBP52 antagonistically regulate GR activity, but a molecular understanding is lacking. Here we present a 3.01 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP52 complex, revealing how FKBP52 integrates into the GR chaperone cycle and directly binds to the active client, potentiating GR activity in vitro and in vivo. We also present a 3.23 Å cryogenic electron microscopy structure of the human GR:Hsp90:FKBP51 complex, revealing how FKBP51 competes with FKBP52 for GR:Hsp90 binding and demonstrating how FKBP51 can act as a potent antagonist to FKBP52. Altogether, we demonstrate how FKBP51 and FKBP52 integrate into the GR chaperone cycle to advance GR to the next stage of maturation. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8ffw.cif.gz | 734.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8ffw.ent.gz | 605.1 KB | Display | PDB format |
PDBx/mmJSON format | 8ffw.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8ffw_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 8ffw_full_validation.pdf.gz | 1.5 MB | Display | |
Data in XML | 8ffw_validation.xml.gz | 66.3 KB | Display | |
Data in CIF | 8ffw_validation.cif.gz | 99.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ff/8ffw ftp://data.pdbj.org/pub/pdb/validation_reports/ff/8ffw | HTTPS FTP |
-Related structure data
Related structure data | 29069MC 8ffvC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 3 types, 4 molecules ABCD
#1: Protein | Mass: 84650.531 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 BL21(DE3) (bacteria) References: UniProt: P07900, non-chaperonin molecular chaperone ATPase #2: Protein | | Mass: 41198.973 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 BL21(DE3) (bacteria) / References: UniProt: P04150 #3: Protein | | Mass: 51158.992 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 BL21(DE3) (bacteria) / References: UniProt: Q13451, peptidylprolyl isomerase |
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-Non-polymers , 3 types, 5 molecules
#4: Chemical | #5: Chemical | #6: Chemical | ChemComp-DEX / | |
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-Details
Has ligand of interest | Y |
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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
Component | Name: Complex of the Glucocorticoid Receptor ligand binding domain, Hsp90 alpha dimer, and the co-chaperone FKBP51 Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
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Molecular weight | Value: 0.3065 MDa / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli BL21(DE3) (bacteria) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283 K |
-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 / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE | |||||||||||||||||||||
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER | |||||||||||||||||||||
Image recording |
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EM imaging optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 171778 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||
Atomic model building | 3D fitting-ID: 1 / Source name: PDB / Type: experimental model
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