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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 | |||||||||
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Title | Structures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist | |||||||||
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![]() | MEMBRANE PROTEIN / GPCR / appetite / energy homeostasis / reward signaling | |||||||||
Function / homology | ![]() 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 / regulation of transmission of nerve impulse / gastric acid secretion / positive regulation of corticotropin secretion / response to follicle-stimulating hormone / positive regulation of cortisol secretion / growth hormone secretion / ghrelin secretion / positive regulation of growth rate / 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 / positive regulation of growth hormone secretion / positive regulation of fatty acid metabolic process / protein tyrosine kinase activator activity / negative regulation of appetite / positive regulation of growth hormone receptor signaling pathway / positive regulation of multicellular organism growth / actin polymerization or depolymerization / cellular response to thyroid hormone stimulus / response to growth hormone / positive regulation of synapse assembly / cartilage development / positive regulation of insulin-like growth factor receptor signaling pathway / response to food / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / negative regulation of interleukin-1 beta production / positive regulation of vascular endothelial cell proliferation / cellular response to insulin-like growth factor stimulus / regulation of postsynapse organization / response to L-glutamate / regulation of synapse assembly / postsynaptic modulation of chemical synaptic transmission / response to dexamethasone / positive regulation of sprouting angiogenesis / dendrite development / negative regulation of endothelial cell proliferation / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / negative regulation of interleukin-6 production / negative regulation of tumor necrosis factor production / decidualization / Synthesis, secretion, and deacylation of Ghrelin / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / positive regulation of adipose tissue development / negative regulation of insulin secretion / regulation of cAMP-mediated signaling / hormone-mediated signaling pathway / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / negative regulation of angiogenesis / response to electrical stimulus / regulation of mitotic spindle organization / cellular response to forskolin / synapse assembly / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / insulin-like growth factor receptor signaling pathway / excitatory postsynaptic potential / response to hormone / synaptic membrane / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / negative regulation of inflammatory response / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / positive regulation of insulin secretion / Schaffer collateral - CA1 synapse / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / cellular response to insulin stimulus / 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 Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
![]() | Liu, H. / Sun, D. / Sun, J. / Zhang, C. | |||||||||
Funding support | ![]()
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![]() | ![]() 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
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 209.6 KB | Display | ![]() |
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PDB format | ![]() | 170.8 KB | Display | ![]() |
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-Validation report
Summary document | ![]() | 801.2 KB | Display | ![]() |
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Full document | ![]() | 810.5 KB | Display | |
Data in XML | ![]() | 36.6 KB | Display | |
Data in CIF | ![]() | 56.5 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 24267MC ![]() 7na8C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 40429.059 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() Production host: Insect expression vector pBlueBacmsGCA1His (others) References: UniProt: P63096 |
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#2: Protein | Mass: 37417.918 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() Production host: Insect expression vector pBlueBacmsGCA1His (others) References: UniProt: P62873 |
#3: Protein | Mass: 7859.173 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() Production host: Insect expression vector pBlueBacmsGCA1His (others) References: UniProt: P59768 |
-Antibody / Protein / Protein/peptide / Non-polymers , 4 types, 5 molecules NRL![](data/chem/img/CLR.gif)
![](data/chem/img/CLR.gif)
#4: Antibody | Mass: 26236.244 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() Production host: Insect expression vector pBlueBacmsGCA1His (others) |
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#5: Protein | Mass: 41406.410 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() Production host: Insect expression vector pBlueBacmsGCA1His (others) References: UniProt: Q92847 |
#6: Protein/peptide | Mass: 1471.657 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) ![]() |
#7: Chemical |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Complex of GHSR-Gi-ghrelin / Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: Insect expression vector pBlueBacmsGCA1His (others) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 82 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 280046 / Symmetry type: POINT |