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Yorodumi- EMDB-24267: Structures of human ghrelin receptor-Gi complexes with ghrelin an... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-24267 | |||||||||
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Title | Structures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist | |||||||||
Map data | cryoEM map of GHSR-Gi-ghrelin | |||||||||
Sample |
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Function / homology | Function and homology information growth hormone secretagogue receptor activity / regulation of hindgut contraction / ghrelin receptor binding / positive regulation of bone development / positive regulation of gastric mucosal blood circulation / regulation of growth hormone secretion / negative regulation of locomotion / growth hormone-releasing hormone receptor activity / cortisol secretion / positive regulation of small intestinal transit ...growth hormone secretagogue receptor activity / regulation of hindgut contraction / ghrelin receptor binding / positive regulation of bone development / positive regulation of gastric mucosal blood circulation / regulation of growth hormone secretion / negative regulation of locomotion / growth hormone-releasing hormone receptor activity / cortisol secretion / positive regulation of small intestinal transit / growth hormone-releasing hormone activity / positive regulation of small intestine smooth muscle contraction / negative regulation of circadian sleep/wake cycle, REM sleep / positive regulation of circadian sleep/wake cycle, non-REM sleep / negative regulation of locomotion involved in locomotory behavior / regulation of response to food / regulation of gastric motility / regulation of transmission of nerve impulse / positive regulation of corticotropin secretion / response to follicle-stimulating hormone / positive regulation of cortisol secretion / growth hormone secretion / ghrelin secretion / gastric acid secretion / positive regulation of growth rate / positive regulation of eating behavior / negative regulation of norepinephrine secretion / positive regulation of appetite / negative regulation of macrophage apoptotic process / adult feeding behavior / positive regulation of growth hormone secretion / negative regulation of appetite / positive regulation of growth hormone receptor signaling pathway / actin polymerization or depolymerization / positive regulation of multicellular organism growth / cellular response to thyroid hormone stimulus / positive regulation of synapse assembly / response to growth hormone / cartilage development / positive regulation of insulin-like growth factor receptor signaling pathway / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / response to food / positive regulation of vascular endothelial cell proliferation / cellular response to insulin-like growth factor stimulus / negative regulation of interleukin-1 beta production / regulation of postsynapse organization / response to L-glutamate / regulation of synapse assembly / positive regulation of fatty acid metabolic process / postsynaptic modulation of chemical synaptic transmission / protein tyrosine kinase activator activity / positive regulation of sprouting angiogenesis / response to dexamethasone / dendrite development / negative regulation of endothelial cell proliferation / positive regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of interleukin-6 production / peptide hormone binding / decidualization / negative regulation of tumor necrosis factor production / Synthesis, secretion, and deacylation of Ghrelin / T cell migration / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / negative regulation of insulin secretion / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / response to electrical stimulus / regulation of mitotic spindle organization / cellular response to forskolin / synapse assembly / positive regulation of adipose tissue development / hormone-mediated signaling pathway / response to hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / negative regulation of angiogenesis / G-protein beta/gamma-subunit complex binding / Peptide ligand-binding receptors / insulin-like growth factor receptor signaling pathway / excitatory postsynaptic potential / synaptic membrane / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / positive regulation of insulin secretion / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Schaffer collateral - CA1 synapse / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
Authors | Liu H / Sun D / Sun J / Zhang C | |||||||||
Funding support | United States, 2 items
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Citation | Journal: Nat Commun / Year: 2021 Title: Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren. Authors: Heng Liu / Dapeng Sun / Alexander Myasnikov / Marjorie Damian / Jean-Louis Baneres / Ji Sun / Cheng Zhang / Abstract: The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its ...The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its agonistic action on GHSR. Synthetic agonists of GHSR are under clinical evaluation for disorders related to appetite and growth hormone dysregulation. Here, we report high-resolution cryo-EM structures of the GHSR-G signaling complex with ghrelin and the non-peptide agonist ibutamoren as an investigational new drug. Our structures together with mutagenesis data reveal the molecular basis for the binding of ghrelin and ibutamoren. Structural comparison suggests a salt bridge and an aromatic cluster near the agonist-binding pocket as important structural motifs in receptor activation. Notable structural variations of the G and GHSR coupling are observed in our cryo-EM analysis. Our results provide a framework for understanding GHSR signaling and developing new GHSR agonist drugs. | |||||||||
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_24267.map.gz | 206.9 MB | EMDB map data format | |
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Header (meta data) | emd-24267-v30.xml emd-24267.xml | 15.7 KB 15.7 KB | Display Display | EMDB header |
Images | emd_24267.png | 47.9 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-24267 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-24267 | HTTPS FTP |
-Validation report
Summary document | emd_24267_validation.pdf.gz | 296.2 KB | Display | EMDB validaton report |
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Full document | emd_24267_full_validation.pdf.gz | 295.7 KB | Display | |
Data in XML | emd_24267_validation.xml.gz | 6.7 KB | Display | |
Data in CIF | emd_24267_validation.cif.gz | 7.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24267 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24267 | HTTPS FTP |
-Related structure data
Related structure data | 7na7MC 7na8C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_24267.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | cryoEM map of GHSR-Gi-ghrelin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.65 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : Complex of GHSR-Gi-ghrelin
Entire | Name: Complex of GHSR-Gi-ghrelin |
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Components |
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-Supramolecule #1: Complex of GHSR-Gi-ghrelin
Supramolecule | Name: Complex of GHSR-Gi-ghrelin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Insect expression vector pBlueBacmsGCA1His (others) |
-Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 40.429059 KDa |
Recombinant expression | Organism: Insect expression vector pBlueBacmsGCA1His (others) |
Sequence | String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TETKNVQFVF DAVTDVIIKN NLKDCGLF |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 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: 37.417918 KDa |
Recombinant expression | Organism: Insect expression vector pBlueBacmsGCA1His (others) |
Sequence | String: MSELDELRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR QGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String: MSELDELRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR QGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPDG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 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: 7.859173 KDa |
Recombinant expression | Organism: Insect expression vector pBlueBacmsGCA1His (others) |
Sequence | String: MASNNTASIA QARKLVQQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASQNP FREKKFFCAI L |
-Macromolecule #4: Antibody fragment
Macromolecule | Name: Antibody fragment / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 26.236244 KDa |
Recombinant expression | Organism: Insect expression vector pBlueBacmsGCA1His (others) |
Sequence | String: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGGSDIVM TQATSSVPVT PGESVSISCR S SKSLLHSN ...String: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGGSDIVM TQATSSVPVT PGESVSISCR S SKSLLHSN GNTYLYWFLQ RPGQSPQLLI YRMSNLASGV PERFSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GA GTKLEL |
-Macromolecule #5: Growth hormone secretagogue receptor type 1
Macromolecule | Name: Growth hormone secretagogue receptor type 1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 41.40641 KDa |
Recombinant expression | Organism: Insect expression vector pBlueBacmsGCA1His (others) |
Sequence | String: MWNATPSEEP GFNLTLADLD WDASPGNDSL GDELLQLFPA PLLAGVTATC VALFVVGIAG NLLTMLVVSR FRELRTTTNL YLSSMAFSD LLIFLCMPLD LVRLWQYRPW NFGDLLCKLF QFVSESCTYA KVLTITALSV ERYFAICFPL RAKVVVTKGR V KLVIFVIW ...String: MWNATPSEEP GFNLTLADLD WDASPGNDSL GDELLQLFPA PLLAGVTATC VALFVVGIAG NLLTMLVVSR FRELRTTTNL YLSSMAFSD LLIFLCMPLD LVRLWQYRPW NFGDLLCKLF QFVSESCTYA KVLTITALSV ERYFAICFPL RAKVVVTKGR V KLVIFVIW AVAFCSAGPI FVLVGVEHEQ GTDPWDTNEC RPTEFAVRSG LLTVMVWVSS IFFFLPVFCL TVLYSLIGRK LW RRRRGDA VVGASLRDQN HKQTVKMLAV VVFAFILCWL PFHVGRYLFS KSFEPGSLEI AQISQYCNLV SFVLFYLSAA INP ILYNIM SKKYRVAVFR LLGFEPFSQR KLSTLKDESS RAWTESSINT |
-Macromolecule #6: Ghrelin-27
Macromolecule | Name: Ghrelin-27 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 1.471657 KDa |
Sequence | String: GS(1IC)FLSPEHQ RV |
-Macromolecule #7: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 2 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-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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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 82.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 280046 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |