+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-29068 | |||||||||
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Title | Cryo-EM structure of the GR-Hsp90-FKBP52 complex | |||||||||
Map data | Sharpened consensus GR-Hsp90-FKBP52 map | |||||||||
Sample |
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Keywords | chaperone / 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 / prostate gland development / steroid hormone binding / PTK6 Expression ...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 / prostate gland development / steroid hormone binding / PTK6 Expression / neuroinflammatory response / glucocorticoid metabolic process / copper ion transport / microglia differentiation / nuclear glucocorticoid receptor binding / mammary gland duct morphogenesis / maternal behavior / protein-containing complex localization / astrocyte differentiation / cellular response to glucocorticoid stimulus / motor behavior / 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 / negative regulation of microtubule polymerization / positive regulation of tau-protein kinase activity / protein insertion into mitochondrial outer membrane / regulation of gluconeogenesis / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / adrenal gland development / Rho GDP-dissociation inhibitor binding / cellular response to steroid hormone stimulus / 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 / regulation of postsynaptic membrane neurotransmitter receptor levels / androgen receptor signaling pathway / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / positive regulation of cell size / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / chaperone-mediated protein complex assembly / protein unfolding / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / estrogen response element binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / axonal growth cone / DNA polymerase binding / chaperone-mediated protein folding / intracellular steroid hormone receptor signaling pathway / core promoter sequence-specific DNA binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of cardiac muscle contraction / Recruitment of mitotic centrosome proteins and complexes / cardiac muscle cell apoptotic process / positive regulation of telomerase activity / Signaling by ERBB2 / positive regulation of defense response to virus by host / cellular response to transforming growth factor beta stimulus / endocytic vesicle lumen / response to salt stress / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / TBP-class protein binding / embryo implantation / steroid binding / activation of innate immune response Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.01 Å | |||||||||
Authors | Noddings CM / Agard DA | |||||||||
Funding support | United States, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_29068.map.gz | 63.8 MB | EMDB map data format | |
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Header (meta data) | emd-29068-v30.xml emd-29068.xml | 31.3 KB 31.3 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_29068_fsc.xml | 12 KB | Display | FSC data file |
Images | emd_29068.png | 70.8 KB | ||
Masks | emd_29068_msk_1.map emd_29068_msk_2.map emd_29068_msk_3.map | 125 MB 125 MB 125 MB | Mask map | |
Filedesc metadata | emd-29068.cif.gz | 7.6 KB | ||
Others | emd_29068_additional_1.map.gz emd_29068_additional_2.map.gz emd_29068_additional_3.map.gz emd_29068_additional_4.map.gz emd_29068_half_map_1.map.gz emd_29068_half_map_2.map.gz | 61.8 MB 117.9 MB 118 MB 117.5 MB 116 MB 116 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-29068 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-29068 | HTTPS FTP |
-Related structure data
Related structure data | 8ffvMC 8ffwC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_29068.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Sharpened consensus GR-Hsp90-FKBP52 map | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.835 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_29068_msk_1.map | ||||||||||||
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Density Histograms |
-Mask #2
File | emd_29068_msk_2.map | ||||||||||||
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Density Histograms |
-Mask #3
File | emd_29068_msk_3.map | ||||||||||||
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Density Histograms |
-Additional map: Unsharpened consensus GR-Hsp90-FKBP52 map
File | emd_29068_additional_1.map | ||||||||||||
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Annotation | Unsharpened consensus GR-Hsp90-FKBP52 map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Focused map on Hsp90 in the GR-Hsp90-FKBP52 complex
File | emd_29068_additional_2.map | ||||||||||||
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Annotation | Focused map on Hsp90 in the GR-Hsp90-FKBP52 complex | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Focused map on GR-FKBP52 in the GR-Hsp90-FKBP52 complex
File | emd_29068_additional_3.map | ||||||||||||
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Annotation | Focused map on GR-FKBP52 in the GR-Hsp90-FKBP52 complex | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Composite map for GR-Hsp90-FKBP52 with combined focused maps...
File | emd_29068_additional_4.map | ||||||||||||
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Annotation | Composite map for GR-Hsp90-FKBP52 with combined focused maps on Hsp90 and GR-FKBP52 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: GR-Hsp90-FKBP52 Half Map 1
File | emd_29068_half_map_1.map | ||||||||||||
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Annotation | GR-Hsp90-FKBP52 Half Map 1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: GR-Hsp90-FKBP52 Half Map 2
File | emd_29068_half_map_2.map | ||||||||||||
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Annotation | GR-Hsp90-FKBP52 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 FKBP52 |
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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 FKBP52 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 307 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 / EC number: non-chaperonin molecular chaperone ATPase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 84.650531 KDa |
Recombinant expression | Organism: Escherichia coli BL21(DE3) (bacteria) |
Sequence | String: PEETQTQDQP MEEEEVETFA FQAEIAQLMS LIINTFYSNK EIFLRELISN SSDALDKIRY ESLTDPSKLD SGKELHINLI PNKQDRTLT IVDTGIGMTK ADLINNLGTI AKSGTKAFME ALQAGADISM IGQFGVGFYS AYLVAEKVTV ITKHNDDEQY A WESSAGGS ...String: PEETQTQDQP MEEEEVETFA FQAEIAQLMS LIINTFYSNK EIFLRELISN SSDALDKIRY ESLTDPSKLD SGKELHINLI PNKQDRTLT IVDTGIGMTK ADLINNLGTI AKSGTKAFME ALQAGADISM IGQFGVGFYS AYLVAEKVTV ITKHNDDEQY A WESSAGGS FTVRTDTGEP MGRGTKVILH LKEDQTEYLE ERRIKEIVKK HSQFIGYPIT LFVEKERDKE VSDDEAEEKE DK EEEKEKE EKESEDKPEI EDVGSDEEEE KKDGDKKKKK KIKEKYIDQE ELNKTKPIWT RNPDDITNEE YGEFYKSLTN DWE DHLAVK HFSVEGQLEF RALLFVPRRA PFDLFENRKK KNNIKLYVRR VFIMDNCEEL IPEYLNFIRG VVDSEDLPLN ISRE MLQQS KILKVIRKNL VKKCLELFTE LAEDKENYKK FYEQFSKNIK LGIHEDSQNR KKLSELLRYY TSASGDEMVS LKDYC TRMK ENQKHIYYIT GETKDQVANS AFVERLRKHG LEVIYMIEPI DEYCVQQLKE FEGKTLVSVT KEGLELPEDE EEKKKQ EEK KTKFENLCKI MKDILEKKVE KVVVSNRLVT SPCCIVTSTY GWTANMERIM KAQALRDNST MGYMAAKKHL EINPDHS II ETLRQKAEAD KNDKSVKDLV ILLYETALLS SGFSLEDPQT HANRIYRMIK LGLGIDEDDP TADDTSAAVT EEMPPLEG D DDTSRMEEVD UniProtKB: Heat shock protein HSP 90-alpha |
-Macromolecule #2: Glucocorticoid receptor
Macromolecule | Name: Glucocorticoid receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 41.198973 KDa |
Recombinant expression | Organism: Escherichia coli BL21(DE3) (bacteria) |
Sequence | String: PKLCLVCSDE ASGCHYGVLT CGSCKVFFKR AVEGQHNYLC AGRNDCIIDK IRRKNCPACR YRKCLQAGMN LEARKTKKKI KGIQQATTG VSQETSENPG NKTIVPATLP QLTPTLVSLL EVIEPEVLYA GYDSSVPDST WRIMTTLNML GGRQVIAAVK W AKAIPGFR ...String: PKLCLVCSDE ASGCHYGVLT CGSCKVFFKR AVEGQHNYLC AGRNDCIIDK IRRKNCPACR YRKCLQAGMN LEARKTKKKI KGIQQATTG VSQETSENPG NKTIVPATLP QLTPTLVSLL EVIEPEVLYA GYDSSVPDST WRIMTTLNML GGRQVIAAVK W AKAIPGFR NLHLDDQMTL LQYSWMSLMA FALGWRSYRQ SSANLLCFAP DLIINEQRMT LPCMYDQCKH MLYVSSELHR LQ VSYEEYL CMKTLLLLSS VPKDGLKSQE LFDEIRMTYI KELGKAIVKR EGNSSQNWQR FYQLTKLLDS MHEVVENLLN YCF QTFLDK TMSIEFPEML AEIITNQIPK YSNGNIKKLL FHQK UniProtKB: Glucocorticoid receptor |
-Macromolecule #3: Peptidyl-prolyl cis-trans isomerase FKBP4, N-terminally processed
Macromolecule | Name: Peptidyl-prolyl cis-trans isomerase FKBP4, N-terminally processed 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: 51.87652 KDa |
Recombinant expression | Organism: Escherichia coli BL21(DE3) (bacteria) |
Sequence | String: MTAEEMKATE SGAQSAPLPM EGVDISPKQD EGVLKVIKRE GTGTEMPMIG DRVFVHYTGW LLDGTKFDSS LDRKDKFSFD LGKGEVIKA WDIAIATMKV GEVCHITCKP EYAYGSAGSP PKIPPNATLV FEVELFEFKG EDLTEEEDGG IIRRIQTRGE G YAKPNEGA ...String: MTAEEMKATE SGAQSAPLPM EGVDISPKQD EGVLKVIKRE GTGTEMPMIG DRVFVHYTGW LLDGTKFDSS LDRKDKFSFD LGKGEVIKA WDIAIATMKV GEVCHITCKP EYAYGSAGSP PKIPPNATLV FEVELFEFKG EDLTEEEDGG IIRRIQTRGE G YAKPNEGA IVEVALEGYY KDKLFDQREL RFEIGEGENL DLPYGLERAI QRMEKGEHSI VYLKPSYAFG SVGKEKFQIP PN AELKYEL HLKSFEKAKE SWEMNSEEKL EQSTIVKERG TVYFKEGKYK QALLQYKKIV SWLEYESSFS NEEAQKAQAL RLA SHLNLA MCHLKLQAFS AAIESCNKAL ELDSNNEKGL FRRGEAHLAV NDFELARADF QKVLQLYPNN KAAKTQLAVC QQRI RRQLA REKKLYANMF ERLAEEENKA KAEASSGDHP TDTEMKEEQK SNTAGSQSQV ETEA UniProtKB: Peptidyl-prolyl cis-trans isomerase FKBP4 |
-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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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000 |
Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 11162 / Average exposure time: 5.9 sec. / Average electron dose: 67.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
-Atomic model buiding 1
Initial model |
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Output model | PDB-8ffv: |