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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 hormone
  • 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 / ghrelin receptor binding / negative regulation of locomotion / regulation of hindgut contraction / positive regulation of bone development / positive regulation of gastric mucosal blood circulation / cortisol secretion / regulation of growth hormone secretion / growth hormone-releasing hormone receptor activity / growth hormone-releasing hormone activity ...growth hormone secretagogue receptor activity / ghrelin receptor binding / negative regulation of locomotion / regulation of hindgut contraction / positive regulation of bone development / positive regulation of gastric mucosal blood circulation / cortisol secretion / regulation of growth hormone secretion / growth hormone-releasing hormone receptor activity / growth hormone-releasing hormone activity / negative regulation of circadian sleep/wake cycle, REM sleep / positive regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of small intestinal transit / regulation of response to food / negative regulation of locomotion involved in locomotory behavior / regulation of gastric motility / regulation of transmission of nerve impulse / positive regulation of corticotropin secretion / neuronal dense core vesicle lumen / positive regulation of cortisol secretion / gastric acid secretion / ghrelin secretion / response to follicle-stimulating hormone / positive regulation of appetite / positive regulation of growth rate / growth hormone secretion / negative regulation of norepinephrine secretion / positive regulation of eating behavior / positive regulation of small intestine smooth muscle contraction / positive regulation of growth hormone secretion / negative regulation of macrophage apoptotic process / adult feeding behavior / positive regulation of growth hormone receptor signaling pathway / negative regulation of appetite / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / actin polymerization or depolymerization / positive regulation of multicellular organism growth / cellular response to thyroid hormone stimulus / vesicle docking involved in exocytosis / response to growth hormone / positive regulation of synapse assembly / positive regulation of insulin-like growth factor receptor signaling pathway / regulation of postsynapse organization / positive regulation of vascular endothelial cell proliferation / cartilage development / response to food / negative regulation of interleukin-1 beta production / G protein-coupled dopamine receptor signaling pathway / positive regulation of fatty acid metabolic process / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / cellular response to insulin-like growth factor stimulus / response to L-glutamate / regulation of synapse assembly / regulation of heart contraction / parallel fiber to Purkinje cell synapse / positive regulation of sprouting angiogenesis / negative regulation of endothelial cell proliferation / response to dexamethasone / dendrite development / negative regulation of interleukin-6 production / peptide hormone binding / protein tyrosine kinase activator activity / positive regulation of insulin secretion involved in cellular response to glucose stimulus / decidualization / negative regulation of tumor necrosis factor production / Synthesis, secretion, and deacylation of Ghrelin / postsynaptic modulation of chemical synaptic transmission / negative regulation of insulin secretion / response to electrical stimulus / synapse assembly / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / positive regulation of adipose tissue development / response to hormone / muscle contraction / hormone-mediated signaling pathway / insulin-like growth factor receptor signaling pathway / negative regulation of angiogenesis / Peptide ligand-binding receptors / excitatory postsynaptic potential / GABA-ergic synapse / locomotory behavior / synaptic membrane / G protein-coupled receptor binding / G protein-coupled receptor activity / Schaffer collateral - CA1 synapse / positive regulation of insulin secretion / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / negative regulation of inflammatory response / Olfactory Signaling Pathway / Activation of the phototransduction cascade / cellular response to insulin stimulus / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / response to estrogen
Similarity search - Function
Preproghrelin peptide / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Growth hormone secretagogue receptor/motilin receptor / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H ...Preproghrelin peptide / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Growth hormone secretagogue receptor/motilin receptor / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / 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. / P-loop containing nucleotide triphosphate hydrolases / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
CHOLESTEROL / G protein subunit alpha o1 / 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
Water00
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


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


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 hormoneCOMPLEX#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 FIELD / 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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