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Yorodumi- EMDB-23004: The GR-Maturation Complex: Glucocorticoid Receptor in complex wit... -
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-Basic information
Entry | Database: EMDB / ID: EMD-23004 | |||||||||
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Title | The GR-Maturation Complex: Glucocorticoid Receptor in complex with Hsp90 and co-chaperone p23 | |||||||||
Map data | Primary map ; GR:Hsp90:p23 ; sharpened, filtered, masked | |||||||||
Sample |
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Keywords | ligand binding / ATP binding / protein folding / cryo-EM / CHAPERONE | |||||||||
Function / homology | Function and homology information lung saccule development / prostaglandin-E synthase / prostaglandin-E synthase activity / telomerase activity / Regulation of NPAS4 gene transcription / nuclear receptor-mediated glucocorticoid signaling pathway / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / Aryl hydrocarbon receptor signalling / steroid hormone binding ...lung saccule development / prostaglandin-E synthase / prostaglandin-E synthase activity / telomerase activity / Regulation of NPAS4 gene transcription / nuclear receptor-mediated glucocorticoid signaling pathway / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / Aryl hydrocarbon receptor signalling / steroid hormone binding / PTK6 Expression / neuroinflammatory response / glucocorticoid metabolic process / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / cyclooxygenase pathway / microglia differentiation / mammary gland duct morphogenesis / maternal behavior / astrocyte differentiation / telomerase holoenzyme complex / glycogen biosynthetic process / cellular response to glucocorticoid stimulus / protein folding chaperone complex / motor behavior / positive regulation of tau-protein kinase activity / prostaglandin biosynthetic process / 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 / skin development / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / adrenal gland development / protein insertion into mitochondrial outer membrane / 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 / : / regulation of postsynaptic membrane neurotransmitter receptor levels / positive regulation of phosphorylation / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / chaperone cofactor-dependent protein refolding / skeletal muscle contraction / Signaling by ERBB2 / telomere maintenance via telomerase / HSF1-dependent transactivation / positive regulation of cell size / response to unfolded protein / protein unfolding / chaperone-mediated protein complex assembly / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / estrogen response element binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / cellular response to dexamethasone stimulus / eNOS activation / axonal growth cone / positive regulation of lamellipodium assembly / DNA polymerase binding / nuclear receptor-mediated steroid hormone signaling pathway / core promoter sequence-specific DNA binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of defense response to virus by host / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / cardiac muscle cell apoptotic process / cellular response to transforming growth factor beta stimulus / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / response to salt stress / positive regulation of cardiac muscle contraction / Anchoring of the basal body to the plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.56 Å | |||||||||
Authors | Noddings CM / Wang Y-R / Agard DA | |||||||||
Funding support | United States, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_23004.map.gz | 7.8 MB | EMDB map data format | |
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Header (meta data) | emd-23004-v30.xml emd-23004.xml | 28.6 KB 28.6 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_23004_fsc.xml | 10.6 KB | Display | FSC data file |
Images | emd_23004.png | 67.8 KB | ||
Masks | emd_23004_msk_1.map emd_23004_msk_2.map | 103 MB 103 MB | Mask map | |
Filedesc metadata | emd-23004.cif.gz | 7.2 KB | ||
Others | emd_23004_additional_1.map.gz emd_23004_additional_2.map.gz emd_23004_additional_3.map.gz emd_23004_half_map_1.map.gz emd_23004_half_map_2.map.gz | 80.6 MB 80.6 MB 80.1 MB 80.8 MB 80.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23004 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23004 | HTTPS FTP |
-Validation report
Summary document | emd_23004_validation.pdf.gz | 810.1 KB | Display | EMDB validaton report |
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Full document | emd_23004_full_validation.pdf.gz | 809.7 KB | Display | |
Data in XML | emd_23004_validation.xml.gz | 17 KB | Display | |
Data in CIF | emd_23004_validation.cif.gz | 21.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23004 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23004 | HTTPS FTP |
-Related structure data
Related structure data | 7krjMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-11028 (Title: Cryo-EM Structures of Glucocorticoid Receptor-Hsp90-p23 [the GR Maturation Complex], Hsp90-p23, and MBP-Hsp90-p23 Data size: 494.1 Data #1: MotionCor2 aligned frames of GR-Hsp90-p23 collected on Gatan K3 [micrographs - single frame] Data #2: Processed subsets [picked particles - single frame - processed]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_23004.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Primary map ; GR:Hsp90:p23 ; sharpened, filtered, masked | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.835 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_23004_msk_1.map | ||||||||||||
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-Mask #2
File | emd_23004_msk_2.map | ||||||||||||
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-Additional map: Raw GR:Hsp90:p23 map
File | emd_23004_additional_1.map | ||||||||||||
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Annotation | Raw GR:Hsp90:p23 map | ||||||||||||
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Density Histograms |
-Additional map: Composite map of GR:Hsp90:p23
File | emd_23004_additional_2.map | ||||||||||||
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Annotation | Composite map of GR:Hsp90:p23 | ||||||||||||
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Density Histograms |
-Additional map: Focused map for GR:Hsp90:p23 ; focused on GR:p23 tail
File | emd_23004_additional_3.map | ||||||||||||
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Annotation | Focused map for GR:Hsp90:p23 ; focused on GR:p23 tail | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: GR:Hsp90:p23 Half Map 1
File | emd_23004_half_map_1.map | ||||||||||||
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Annotation | GR:Hsp90:p23 Half Map 1 | ||||||||||||
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-Half map: GR:Hsp90:p23 Half Map 2
File | emd_23004_half_map_2.map | ||||||||||||
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Annotation | GR:Hsp90:p23 Half Map 2 | ||||||||||||
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Density Histograms |
-Sample components
-Entire : Complex of the Glucocorticoid Receptor ligand binding domain, Hsp...
Entire | Name: Complex of the Glucocorticoid Receptor ligand binding domain, Hsp90 alpha dimer, and the co-chaperone p23 |
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Components |
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-Supramolecule #1: Complex of the Glucocorticoid Receptor ligand binding domain, Hsp...
Supramolecule | Name: Complex of the Glucocorticoid Receptor ligand binding domain, Hsp90 alpha dimer, and the co-chaperone p23 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 263 KDa |
-Macromolecule #1: Heat shock protein HSP 90-alpha
Macromolecule | Name: Heat shock protein HSP 90-alpha / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 84.781727 KDa |
Recombinant expression | Organism: Escherichia coli BL21 (bacteria) |
Sequence | String: MPEETQTQDQ PMEEEEVETF AFQAEIAQLM SLIINTFYSN KEIFLRELIS NSSDALDKIR YESLTDPSKL DSGKELHINL IPNKQDRTL TIVDTGIGMT KADLINNLGT IAKSGTKAFM EALQAGADIS MIGQFGVGFY SAYLVAEKVT VITKHNDDEQ Y AWESSAGG ...String: MPEETQTQDQ PMEEEEVETF AFQAEIAQLM SLIINTFYSN KEIFLRELIS NSSDALDKIR YESLTDPSKL DSGKELHINL IPNKQDRTL TIVDTGIGMT KADLINNLGT IAKSGTKAFM EALQAGADIS MIGQFGVGFY SAYLVAEKVT VITKHNDDEQ Y AWESSAGG SFTVRTDTGE PMGRGTKVIL HLKEDQTEYL EERRIKEIVK KHSQFIGYPI TLFVEKERDK EVSDDEAEEK ED KEEEKEK EEKESEDKPE IEDVGSDEEE EKKDGDKKKK KKIKEKYIDQ EELNKTKPIW TRNPDDITNE EYGEFYKSLT NDW EDHLAV KHFSVEGQLE FRALLFVPRR APFDLFENRK KKNNIKLYVR RVFIMDNCEE LIPEYLNFIR GVVDSEDLPL NISR EMLQQ SKILKVIRKN LVKKCLELFT ELAEDKENYK KFYEQFSKNI KLGIHEDSQN RKKLSELLRY YTSASGDEMV SLKDY CTRM KENQKHIYYI TGETKDQVAN SAFVERLRKH GLEVIYMIEP IDEYCVQQLK EFEGKTLVSV TKEGLELPED EEEKKK QEE KKTKFENLCK IMKDILEKKV EKVVVSNRLV TSPCCIVTST YGWTANMERI MKAQALRDNS TMGYMAAKKH LEINPDH SI IETLRQKAEA DKNDKSVKDL VILLYETALL SSGFSLEDPQ THANRIYRMI KLGLGIDEDD PTADDTSAAV TEEMPPLE G DDDTSRMEEV D UniProtKB: Heat shock protein HSP 90-alpha |
-Macromolecule #2: Prostaglandin E synthase 3
Macromolecule | Name: Prostaglandin E synthase 3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: prostaglandin-E synthase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 18.720395 KDa |
Recombinant expression | Organism: Escherichia coli BL21 (bacteria) |
Sequence | String: MQPASAKWYD RRDYVFIEFC VEDSKDVNVN FEKSKLTFSC LGGSDNFKHL NEIDLFHCID PNDSKHKRTD RSILCCLRKG ESGQSWPRL TKERAKLNWL SVDFNNWKDW EDDSDEDMSN FDRFSEMMNN MGGDEDVDLP EVDGADDDSQ DSDDEKMPDL E UniProtKB: Prostaglandin E synthase 3 |
-Macromolecule #3: Glucocorticoid receptor
Macromolecule | Name: Glucocorticoid receptor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 29.924867 KDa |
Recombinant expression | Organism: Escherichia coli BL21 (bacteria) |
Sequence | String: IVPATLPQLT PTLVSLLEVI EPEVLYAGYD SSVPDSTWRI MTTLNMLGGR QVIAAVKWAK AIPGFRNLHL DDQMTLLQYS WMSLMAFAL GWRSYRQSSA NLLCFAPDLI INEQRMTLPC MYDQCKHMLY VSSELHRLQV SYEEYLCMKT LLLLSSVPKD G LKSQELFD ...String: IVPATLPQLT PTLVSLLEVI EPEVLYAGYD SSVPDSTWRI MTTLNMLGGR QVIAAVKWAK AIPGFRNLHL DDQMTLLQYS WMSLMAFAL GWRSYRQSSA NLLCFAPDLI INEQRMTLPC MYDQCKHMLY VSSELHRLQV SYEEYLCMKT LLLLSSVPKD G LKSQELFD EIRMTYIKEL GKAIVKREGN SSQNWQRFYQ LTKLLDSMHE VVENLLNYCF QTFLDKTMSI EFPEMLAEII TN QIPKYSN GNIKKLLFHQ K UniProtKB: Glucocorticoid receptor |
-Macromolecule #4: ADENOSINE-5'-TRIPHOSPHATE
Macromolecule | Name: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: ATP |
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Molecular weight | Theoretical: 507.181 Da |
Chemical component information | ChemComp-ATP: |
-Macromolecule #5: MAGNESIUM ION
Macromolecule | Name: MAGNESIUM ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: MG |
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Molecular weight | Theoretical: 24.305 Da |
-Macromolecule #6: DEXAMETHASONE
Macromolecule | Name: DEXAMETHASONE / type: ligand / ID: 6 / Number of copies: 1 / Formula: DEX |
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Molecular weight | Theoretical: 392.461 Da |
Chemical component information | ChemComp-DEX: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 5608 / Average exposure time: 5.9 sec. / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Initial model |
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Output model | PDB-7krj: |