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- PDB-8ffv: Cryo-EM structure of the GR-Hsp90-FKBP52 complex -

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Basic information

Entry
Database: PDB / ID: 8ffv
TitleCryo-EM structure of the GR-Hsp90-FKBP52 complex
Components
  • Glucocorticoid receptor
  • Heat shock protein HSP 90-alpha
  • Peptidyl-prolyl cis-trans isomerase FKBP4, N-terminally processed
KeywordsCHAPERONE / steroid hormone receptor / ligand binding / ATP binding / protein folding
Function / homology
Function and homology information


steroid hormone receptor complex assembly / negative regulation of microtubule polymerization or depolymerization / male sex differentiation / copper-dependent protein binding / Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / glucocorticoid metabolic process / prostate gland development / steroid hormone binding ...steroid hormone receptor complex assembly / negative regulation of microtubule polymerization or depolymerization / male sex differentiation / copper-dependent protein binding / Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / glucocorticoid metabolic process / prostate gland development / steroid hormone binding / PTK6 Expression / copper ion transport / neuroinflammatory response / mammary gland duct morphogenesis / response to cortisol / nuclear glucocorticoid receptor binding / microglia differentiation / astrocyte differentiation / maternal behavior / protein-containing complex localization / adrenal gland development / regulation of gluconeogenesis / cellular response to glucocorticoid stimulus / androgen receptor signaling pathway / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / cellular response to steroid hormone stimulus / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / dATP binding / sperm plasma membrane / chaperone-mediated autophagy / FK506 binding / mitochondrial transport / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / telomerase holoenzyme complex assembly / 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 / Uptake and function of diphtheria toxin / protein import into mitochondrial matrix / dendritic growth cone / negative regulation of microtubule polymerization / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / motor behavior / non-chaperonin molecular chaperone ATPase / Assembly and release of respiratory syncytial virus (RSV) virions / nuclear receptor-mediated steroid hormone signaling pathway / positive regulation of cell size / protein unfolding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / estrogen response element binding / cellular response to dexamethasone stimulus / HSF1-dependent transactivation / protein folding chaperone complex / response to unfolded protein / regulation of protein-containing complex assembly / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Attenuation phase / enzyme-substrate adaptor activity / HSF1 activation / cellular response to transforming growth factor beta stimulus / neurofibrillary tangle assembly / chaperone-mediated protein complex assembly / axonal growth cone / RHOBTB2 GTPase cycle / telomere maintenance via telomerase / regulation of postsynaptic membrane neurotransmitter receptor levels / core promoter sequence-specific DNA binding / nitric oxide metabolic process / positive regulation of lamellipodium assembly / steroid binding / embryo implantation / skeletal muscle contraction / positive regulation of defense response to virus by host / Signaling by ERBB2 / eNOS activation / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of telomere maintenance via telomerase / response to salt stress / cardiac muscle cell apoptotic process / heat shock protein binding / endocytic vesicle lumen / DNA polymerase binding / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome
Similarity search - Function
Tetratricopeptide repeat 2 / Tetratricopeptide repeat / Glucocorticoid receptor / Glucocorticoid receptor / : / Tetratricopeptide repeat / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal ...Tetratricopeptide repeat 2 / Tetratricopeptide repeat / Glucocorticoid receptor / Glucocorticoid receptor / : / 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 / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / TPR repeat region circular profile. / Peptidyl-prolyl cis-trans isomerase domain superfamily / TPR repeat profile. / Tetratricopeptide repeats / Tetratricopeptide repeat / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / 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'-TRIPHOSPHATE / DEXAMETHASONE / Glucocorticoid receptor / Heat shock protein HSP 90-alpha / Peptidyl-prolyl cis-trans isomerase FKBP4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 Å
AuthorsNoddings, C.M. / Agard, D.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM118099 United States
CitationJournal: 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
DepositionDec 10, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 1, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2023Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.title
Revision 1.2Nov 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Dec 20, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Heat shock protein HSP 90-alpha
B: Heat shock protein HSP 90-alpha
C: Glucocorticoid receptor
D: Peptidyl-prolyl cis-trans isomerase FKBP4, N-terminally processed
hetero molecules


Theoretical massNumber of molelcules
Total (without water)263,8329
Polymers262,3774
Non-polymers1,4555
Water00
1


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

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Components

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Protein , 3 types, 4 molecules ABCD

#1: Protein Heat shock protein HSP 90-alpha / Heat shock 86 kDa / HSP 86 / HSP86 / Lipopolysaccharide-associated protein 2 / LAP-2 / LPS- ...Heat shock 86 kDa / HSP 86 / HSP86 / Lipopolysaccharide-associated protein 2 / LAP-2 / LPS-associated protein 2 / Renal carcinoma antigen NY-REN-38


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 / Plasmid: pET151 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P07900, non-chaperonin molecular chaperone ATPase
#2: Protein Glucocorticoid receptor / GR / Nuclear receptor subfamily 3 group C member 1


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 Peptidyl-prolyl cis-trans isomerase FKBP4, N-terminally processed


Mass: 51876.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP4, FKBP52 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q02790

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Non-polymers , 3 types, 5 molecules

#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-DEX / DEXAMETHASONE / 9A-FLUORO-16BETA-METHYLPREDNISOLONE


Mass: 392.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29FO5 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: Complex of the Glucocorticoid Receptor ligand binding domain, Hsp90 alpha dimer, and the co-chaperone FKBP52
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.307 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283 K

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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 / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 5.9 sec. / Electron dose: 67 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 11162
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
2SerialEM4image acquisition
4CTFFIND4.1CTF correction
9RELION3.0.8initial Euler assignment
10RELION3.0.8final Euler assignment
11RELION3.0.8classification
12cryoSPARC3.3.23D reconstruction
13Rosetta3.11model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 307109 / Symmetry type: POINT
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeInitial refinement model-ID
15FWK

5fwk

A5FWK1
25FWK

5fwk

B5FWK1
31M2Z

1m2z

A1M2Z2
41EJF

1ejf

A1EJF3

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