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- PDB-7krj: The GR-Maturation Complex: Glucocorticoid Receptor in complex wit... -

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Basic information

Entry
Database: PDB / ID: 7krj
TitleThe GR-Maturation Complex: Glucocorticoid Receptor in complex with Hsp90 and co-chaperone p23
Components
  • Glucocorticoid receptor
  • Heat shock protein HSP 90-alpha
  • Prostaglandin E synthase 3
KeywordsCHAPERONE / ligand binding / ATP binding / protein folding / cryo-EM
Function / homology
Function and homology information


prostaglandin-E synthase / prostaglandin-E synthase activity / Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / telomerase activity / prostanoid biosynthetic process / Aryl hydrocarbon receptor signalling / steroid hormone binding / glucocorticoid metabolic process ...prostaglandin-E synthase / prostaglandin-E synthase activity / Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / telomerase activity / prostanoid biosynthetic process / Aryl hydrocarbon receptor signalling / steroid hormone binding / glucocorticoid metabolic process / response to cortisol / PTK6 Expression / neuroinflammatory response / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / mammary gland duct morphogenesis / microglia differentiation / maternal behavior / astrocyte differentiation / telomerase holoenzyme complex / prostaglandin biosynthetic process / protein folding chaperone complex / adrenal gland development / regulation of gluconeogenesis / cellular response to glucocorticoid stimulus / sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / cellular response to steroid hormone stimulus / sperm plasma membrane / chaperone-mediated autophagy / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / mitochondrial transport / Uptake and function of diphtheria toxin / 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 / protein import into mitochondrial matrix / dendritic growth cone / TPR domain binding / motor behavior / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / : / protein unfolding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / estrogen response element binding / positive regulation of cell size / HSF1-dependent transactivation / response to unfolded protein / cellular response to dexamethasone stimulus / enzyme-substrate adaptor activity / skeletal muscle contraction / nuclear receptor-mediated steroid hormone signaling pathway / regulation of protein-containing complex assembly / HSF1 activation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Attenuation phase / cellular response to transforming growth factor beta stimulus / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / RHOBTB2 GTPase cycle / regulation of postsynaptic membrane neurotransmitter receptor levels / telomere maintenance via telomerase / axonal growth cone / core promoter sequence-specific DNA binding / positive regulation of lamellipodium assembly / nitric oxide metabolic process / eNOS activation / positive regulation of defense response to virus by host / DNA polymerase binding / steroid binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / response to salt stress / positive regulation of telomere maintenance via telomerase / Signaling by ERBB2 / cardiac muscle cell apoptotic process / 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 / Recruitment of mitotic centrosome proteins and complexes / activation of innate immune response / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes
Similarity search - Function
Co-chaperone protein p23-like / CS domain / CS domain / CS domain profile. / Immunoglobulin-like - #790 / Glucocorticoid receptor / Glucocorticoid receptor / HSP20-like chaperone / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. ...Co-chaperone protein p23-like / CS domain / CS domain / CS domain profile. / Immunoglobulin-like - #790 / Glucocorticoid receptor / Glucocorticoid receptor / HSP20-like chaperone / 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 / : / Retinoid X Receptor / Retinoid X Receptor / Histidine kinase-like ATPases / 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 / Ribosomal protein S5 domain 2-type fold / Immunoglobulin-like / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / DEXAMETHASONE / Glucocorticoid receptor / Heat shock protein HSP 90-alpha / Prostaglandin E synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.56 Å
AuthorsNoddings, C.M. / Wang, Y.-R. / Agard, D.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM118099 United States
CitationJournal: Nature / Year: 2022
Title: Structure of Hsp90-p23-GR reveals the Hsp90 client-remodelling mechanism.
Authors: Chari M Noddings / Ray Yu-Ruei Wang / Jill L Johnson / David A Agard /
Abstract: Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins. The glucocorticoid receptor (GR) is a model client that constantly ...Hsp90 is a conserved and essential molecular chaperone responsible for the folding and activation of hundreds of 'client' proteins. The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity. GR ligand binding was previously shown to nr inhibited by Hsp70 and restored by Hsp90, aided by the co-chaperone p23. However, a molecular understanding of the chaperone-mediated remodelling that occurs between the inactive Hsp70-Hsp90 'client-loading complex' and an activated Hsp90-p23 'client-maturation complex' is lacking for any client, including GR. Here we present a cryo-electron microscopy (cryo-EM) structure of the human GR-maturation complex (GR-Hsp90-p23), revealing that the GR ligand-binding domain is restored to a folded, ligand-bound conformation, while being simultaneously threaded through the Hsp90 lumen. In addition, p23 directly stabilizes native GR using a C-terminal helix, resulting in enhanced ligand binding. This structure of a client bound to Hsp90 in a native conformation contrasts sharply with the unfolded kinase-Hsp90 structure. Thus, aided by direct co-chaperone-client interactions, Hsp90 can directly dictate client-specific folding outcomes. Together with the GR-loading complex structure, we present the molecular mechanism of chaperone-mediated GR remodelling, establishing the first, to our knowledge, complete chaperone cycle for any Hsp90 client.
History
DepositionNov 20, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 26, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2May 29, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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Structure visualization

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  • Deposited structure unit
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Heat shock protein HSP 90-alpha
B: Heat shock protein HSP 90-alpha
C: Prostaglandin E synthase 3
D: Glucocorticoid receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)219,6649
Polymers218,2094
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 / 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 BL21 (bacteria) / References: UniProt: P07900
#2: 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 BL21 (bacteria) / References: UniProt: Q15185, prostaglandin-E synthase
#3: Protein Glucocorticoid receptor / GR / Nuclear receptor subfamily 3 group C member 1


Mass: 29924.867 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 (bacteria) / References: UniProt: P04150

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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 / 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
#6: Chemical ChemComp-DEX / DEXAMETHASONE / 9A-FLUORO-16BETA-METHYLPREDNISOLONE


Mass: 392.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29FO5

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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

ComponentName: Complex of the Glucocorticoid Receptor ligand binding domain, Hsp90 alpha dimer, and the co-chaperone p23
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.263 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21 (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: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 5608
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
2SerialEMimage acquisition
4CTFFIND4.1CTF correction
9RELION3.0.8initial Euler assignment
10RELION3.0.8final Euler assignment
11RELION3.0.8classification
12RELION3.0.83D reconstruction
13Rosettamodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6062152
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.56 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 140217 / 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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