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- PDB-7na7: Structures of human ghrelin receptor-Gi complexes with ghrelin an... -

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Basic information

Entry
Database: PDB / ID: 7na7
TitleStructures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment
  • Ghrelin-27
  • Growth hormone secretagogue receptor type 1
KeywordsMEMBRANE PROTEIN / GPCR / appetite / energy homeostasis / reward signaling
Function / homology
Function and homology information


ghrelin receptor binding / negative regulation of locomotion / positive regulation of bone development / positive regulation of gastric mucosal blood circulation / cortisol secretion / growth hormone secretagogue receptor activity / regulation of hindgut contraction / growth hormone-releasing hormone activity / negative regulation of circadian sleep/wake cycle, REM sleep / regulation of growth hormone secretion ...ghrelin receptor binding / negative regulation of locomotion / positive regulation of bone development / positive regulation of gastric mucosal blood circulation / cortisol secretion / growth hormone secretagogue receptor activity / regulation of hindgut contraction / growth hormone-releasing hormone activity / negative regulation of circadian sleep/wake cycle, REM sleep / regulation of growth hormone secretion / regulation of response to food / negative regulation of locomotion involved in locomotory behavior / growth hormone-releasing hormone receptor activity / positive regulation of small intestinal transit / regulation of gastric motility / response to follicle-stimulating hormone / regulation of transmission of nerve impulse / positive regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of cortisol secretion / positive regulation of corticotropin secretion / ghrelin secretion / positive regulation of growth rate / positive regulation of appetite / growth hormone secretion / gastric acid secretion / negative regulation of norepinephrine secretion / negative regulation of macrophage apoptotic process / neuronal dense core vesicle lumen / positive regulation of small intestine smooth muscle contraction / positive regulation of eating behavior / adult feeding behavior / positive regulation of growth hormone secretion / positive regulation of growth hormone receptor signaling pathway / negative regulation of appetite / actin polymerization or depolymerization / positive regulation of multicellular organism growth / cellular response to thyroid hormone stimulus / cartilage development / positive regulation of insulin-like growth factor receptor signaling pathway / positive regulation of vascular endothelial cell proliferation / response to growth hormone / regulation of postsynapse organization / response to L-glutamate / positive regulation of synapse assembly / negative regulation of interleukin-1 beta production / response to food / positive regulation of fatty acid metabolic process / response to dexamethasone / cellular response to insulin-like growth factor stimulus / regulation of synapse assembly / positive regulation of sprouting angiogenesis / negative regulation of endothelial cell proliferation / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / dendrite development / decidualization / negative regulation of interleukin-6 production / peptide hormone binding / protein tyrosine kinase activator activity / response to electrical stimulus / negative regulation of tumor necrosis factor production / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of insulin secretion involved in cellular response to glucose stimulus / postsynaptic modulation of chemical synaptic transmission / adenylate cyclase inhibitor activity / response to hormone / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / positive regulation of adipose tissue development / synapse assembly / response to prostaglandin E / D2 dopamine receptor binding / hormone-mediated signaling pathway / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / insulin-like growth factor receptor signaling pathway / cellular response to forskolin / Peptide ligand-binding receptors / negative regulation of angiogenesis / synaptic membrane / regulation of mitotic spindle organization / excitatory postsynaptic potential / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / positive regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to peptide hormone / negative regulation of inflammatory response / response to estrogen / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / Schaffer collateral - CA1 synapse / G-protein beta/gamma-subunit complex binding / cellular response to insulin stimulus / glucose metabolic process / Olfactory Signaling Pathway
Similarity search - Function
Preproghrelin peptide / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Growth hormone secretagogue receptor/motilin receptor / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 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 / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
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 / Appetite-regulating hormone
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, 2items
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
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

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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
L: Ghrelin-27
hetero molecules


Theoretical massNumber of molelcules
Total (without water)155,5948
Polymers154,8206
Non-polymers7732
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14120 Å2
ΔGint-68 kcal/mol
Surface area47760 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 / Protein/peptide / Non-polymers , 4 types, 5 molecules NRL

#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: 41406.410 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
#6: Protein/peptide Ghrelin-27


Mass: 1471.657 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UBU3
#7: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION

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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

ComponentName: Complex of GHSR-Gi-ghrelin / Type: COMPLEX / Entity ID: #1-#6 / 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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 280046 / Symmetry type: POINT

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