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- PDB-7na8: Structures of human ghrelin receptor-Gi complexes with ghrelin an... -

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Basic information

Entry
Database: PDB / ID: 7na8
TitleStructures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment
  • Growth hormone secretagogue receptor type 1
KeywordsMEMBRANE PROTEIN / GPCR / appetite / energy homeostasis / reward signaling
Function / homology
Function and homology information


growth hormone secretagogue receptor activity / regulation of hindgut contraction / regulation of growth hormone secretion / growth hormone-releasing hormone receptor activity / positive regulation of small intestinal transit / negative regulation of locomotion involved in locomotory behavior / regulation of gastric motility / regulation of transmission of nerve impulse / response to follicle-stimulating hormone / ghrelin secretion ...growth hormone secretagogue receptor activity / regulation of hindgut contraction / regulation of growth hormone secretion / growth hormone-releasing hormone receptor activity / positive regulation of small intestinal transit / negative regulation of locomotion involved in locomotory behavior / regulation of gastric motility / regulation of transmission of nerve impulse / response to follicle-stimulating hormone / ghrelin secretion / growth hormone secretion / positive regulation of eating behavior / negative regulation of norepinephrine secretion / positive regulation of small intestine smooth muscle contraction / positive regulation of appetite / negative regulation of macrophage apoptotic process / adult feeding behavior / negative regulation of appetite / actin polymerization or depolymerization / positive regulation of multicellular organism growth / cellular response to thyroid hormone stimulus / response to growth hormone / positive regulation of insulin-like growth factor receptor signaling pathway / response to food / positive regulation of vascular endothelial cell proliferation / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / negative regulation of interleukin-1 beta production / response to L-glutamate / regulation of postsynapse organization / regulation of synapse assembly / positive regulation of fatty acid metabolic process / cellular response to insulin-like growth factor stimulus / postsynaptic modulation of chemical synaptic transmission / positive regulation of sprouting angiogenesis / response to dexamethasone / peptide hormone binding / negative regulation of interleukin-6 production / decidualization / negative regulation of tumor necrosis factor production / T cell migration / Adenylate cyclase inhibitory pathway / negative regulation of insulin secretion / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / hormone-mediated signaling pathway / response to hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / insulin-like growth factor receptor signaling pathway / synaptic membrane / Regulation of insulin secretion / 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 / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Schaffer collateral - CA1 synapse / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / 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 / Prostacyclin signalling through prostacyclin receptor / response to peptide hormone / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / negative regulation of inflammatory response / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to insulin stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle
Similarity search - Function
Growth hormone secretagogue receptor/motilin receptor / G-protein alpha subunit, group I / 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 ...Growth hormone secretagogue receptor/motilin receptor / G-protein alpha subunit, group I / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-1KD / CHOLESTEROL / 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 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Growth hormone secretagogue receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsLiu, H. / Sun, D. / Sun, J. / Zhang, C.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM128641 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R03TR003306 United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)HL143037 United States
CitationJournal: 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
DepositionJun 20, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 15, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Antibody fragment
R: Growth hormone secretagogue receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)154,2507
Polymers153,3355
Non-polymers9152
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area11470 Å2
ΔGint-63 kcal/mol
Surface area46680 Å2

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Components

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

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40429.059 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1
Production host: Insect expression vector pBlueBacmsGCA1His (others)
References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37417.918 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1
Production host: Insect expression vector pBlueBacmsGCA1His (others)
References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7859.173 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2
Production host: Insect expression vector pBlueBacmsGCA1His (others)
References: UniProt: P59768

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Antibody / Protein , 2 types, 2 molecules NR

#4: Antibody Antibody fragment


Mass: 26236.244 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse)
Production host: Insect expression vector pBlueBacmsGCA1His (others)
#5: Protein Growth hormone secretagogue receptor type 1 / GHS-R / GH-releasing peptide receptor / GHRP / Ghrelin receptor


Mass: 41392.383 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GHSR
Production host: Insect expression vector pBlueBacmsGCA1His (others)
References: UniProt: Q92847

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Non-polymers , 2 types, 2 molecules

#6: Chemical ChemComp-1KD / 1-(methanesulfonyl)-1'-(2-methyl-L-alanyl-O-benzyl-D-seryl)-1,2-dihydrospiro[indole-3,4'-piperidine]


Mass: 528.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H36N4O5S / Feature type: SUBJECT OF INVESTIGATION / Comment: agonist, hormone*YM
#7: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestY
Has protein modificationY

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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

ComponentName: Complex of GHSR-Gi-ghrelin / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Insect expression vector pBlueBacmsGCA1His (others)
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
Image recordingElectron dose: 82 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: dev_3951: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 283300 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049086
ELECTRON MICROSCOPYf_angle_d0.60712303
ELECTRON MICROSCOPYf_dihedral_angle_d8.0741231
ELECTRON MICROSCOPYf_chiral_restr0.0451388
ELECTRON MICROSCOPYf_plane_restr0.0041547

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