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- PDB-7w2z: Cryo-EM structure of the ghrelin-bound human ghrelin receptor-Go ... -

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Basic information

Entry
Database: PDB / ID: 7w2z
TitleCryo-EM structure of the ghrelin-bound human ghrelin receptor-Go complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Appetite-regulating hormoneGhrelin
  • Growth hormone secretagogue receptor type 1
  • ScFv16
KeywordsSIGNALING PROTEIN / GPCR / Ghrelin / endogenous agonist / Class A GPCR / Peptide receptor
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 / 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 / guanyl nucleotide binding / regulation of transmission of nerve impulse / gastric acid secretion / positive regulation of corticotropin secretion / positive regulation of cortisol secretion / growth hormone secretion / response to follicle-stimulating hormone / ghrelin secretion / positive regulation of growth rate / positive regulation of eating behavior / negative regulation of norepinephrine secretion / positive regulation of appetite / positive regulation of small intestine smooth muscle contraction / negative regulation of macrophage apoptotic process / adult feeding behavior / positive regulation of growth hormone secretion / negative regulation of appetite / mu-type opioid receptor binding / positive regulation of growth hormone receptor signaling pathway / corticotropin-releasing hormone receptor 1 binding / positive regulation of multicellular organism growth / actin polymerization or depolymerization / 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 postsynapse organization / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / cellular response to insulin-like growth factor stimulus / response to food / response to L-glutamate / positive regulation of vascular endothelial cell proliferation / negative regulation of interleukin-1 beta production / regulation of synapse assembly / dopamine receptor signaling pathway / positive regulation of fatty acid metabolic process / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell proliferation / response to dexamethasone / protein tyrosine kinase activator activity / dendrite development / positive regulation of sprouting angiogenesis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / negative regulation of interleukin-6 production / decidualization / negative regulation of tumor necrosis factor production / negative regulation of insulin secretion / Synthesis, secretion, and deacylation of Ghrelin / G protein-coupled serotonin receptor binding / response to electrical stimulus / synapse assembly / positive regulation of adipose tissue development / excitatory postsynaptic potential / hormone-mediated signaling pathway / Peptide ligand-binding receptors / response to hormone / negative regulation of angiogenesis / insulin-like growth factor receptor signaling pathway / synaptic membrane / muscle contraction / G protein-coupled receptor binding / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Schaffer collateral - CA1 synapse / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / positive regulation of insulin secretion / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)
Similarity search - Function
Preproghrelin peptide / Growth hormone secretagogue receptor/motilin receptor / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Motilin/ghrelin-associated peptide / Motilin/ghrelin / G-protein alpha subunit, group I / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion ...Preproghrelin peptide / Growth hormone secretagogue receptor/motilin receptor / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Motilin/ghrelin-associated peptide / Motilin/ghrelin / G-protein alpha subunit, group I / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
CHOLESTEROL / Guanine nucleotide-binding protein G(o) subunit alpha / Guanine nucleotide-binding protein G(o) subunit alpha / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Growth hormone secretagogue receptor type 1 / Appetite-regulating hormone
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsQin, J. / Ming, Q. / Ji, S. / Mao, C. / Shen, D. / Zhang, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2022
Title: Molecular mechanism of agonism and inverse agonism in ghrelin receptor.
Authors: Jiao Qin / Ye Cai / Zheng Xu / Qianqian Ming / Su-Yu Ji / Chao Wu / Huibing Zhang / Chunyou Mao / Dan-Dan Shen / Kunio Hirata / Yanbin Ma / Wei Yan / Yan Zhang / Zhenhua Shao /
Abstract: Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are ...Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.
History
DepositionNov 24, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 19, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(o) subunit alpha
R: Growth hormone secretagogue receptor type 1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: ScFv16
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
L: Appetite-regulating hormone
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,3498
Polymers141,5766
Non-polymers7732
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13980 Å2
ΔGint-67 kcal/mol
Surface area50540 Å2

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules AGB

#1: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 26456.100 Da / Num. of mol.: 1 / Mutation: G42D,E43N,A227D,G230D,I332A,V335I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A1W2PS82, UniProt: P09471
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37285.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873

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Protein / Antibody / Protein/peptide / Non-polymers , 4 types, 5 molecules RSL

#2: Protein Growth hormone secretagogue receptor type 1 / GHS-R / GH-releasing peptide receptor / GHRP / Ghrelin receptor


Mass: 41364.309 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GHSR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92847
#4: Antibody ScFv16


Mass: 26610.615 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Protein/peptide Appetite-regulating hormone / Ghrelin


Mass: 1998.288 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GHRL / Production host: synthetic construct (others) / References: UniProt: Q9UBU3
#7: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O

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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

Component
IDNameTypeEntity IDParent-IDSource
1Cryo-EM structure of the ghrelin-bound human ghrelin receptor-Go complexCOMPLEX#1-#60RECOMBINANT
2Guanine nucleotide-binding protein G(o) subunit alpha, Growth hormone secretagogue receptor type 1COMPLEX#11RECOMBINANT
3Guanine nucleotide-binding proteinCOMPLEX#2-#3, #51RECOMBINANT
4ScFv16COMPLEX#41RECOMBINANT
5Appetite-regulating hormoneGhrelinCOMPLEX#61RECOMBINANT
Molecular weightValue: 160.4 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43synthetic construct (others)32630
54Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Spodoptera frugiperda (fall armyworm)7108
21Spodoptera frugiperda (fall armyworm)7108
32Spodoptera frugiperda (fall armyworm)7108
43Spodoptera frugiperda (fall armyworm)7108
54synthetic construct (others)32630
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 62.24 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 230306 / Symmetry type: POINT
RefinementHighest resolution: 2.8 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0099275
ELECTRON MICROSCOPYf_angle_d1.04512573
ELECTRON MICROSCOPYf_dihedral_angle_d16.2985514
ELECTRON MICROSCOPYf_chiral_restr0.0631437
ELECTRON MICROSCOPYf_plane_restr0.0081580

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