[English] 日本語
Yorodumi- PDB-7na8: Structures of human ghrelin receptor-Gi complexes with ghrelin an... -
+Open data
-Basic information
Entry | Database: PDB / ID: 7na8 | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Title | Structures of human ghrelin receptor-Gi complexes with ghrelin and a synthetic agonist | ||||||||||||
Components |
| ||||||||||||
Keywords | MEMBRANE 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 / growth hormone 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 / growth hormone secretion / ghrelin 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 / positive regulation of fatty acid metabolic process / negative regulation of appetite / positive regulation of multicellular organism growth / actin polymerization or depolymerization / cellular response to thyroid hormone stimulus / response to growth hormone / 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 / peptide hormone binding / negative regulation of interleukin-6 production / negative regulation of tumor necrosis factor production / decidualization / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / negative regulation of insulin secretion / regulation of cAMP-mediated signaling / hormone-mediated signaling pathway / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / insulin-like growth factor receptor signaling pathway / 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 / 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 / G beta:gamma signalling through CDC42 / response to peptide hormone / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å | ||||||||||||
Authors | Liu, H. / Sun, D. / Sun, J. / Zhang, C. | ||||||||||||
Funding support | United States, 3items
| ||||||||||||
Citation | Journal: 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 |
|
-Structure visualization
Movie |
Movie viewer |
---|---|
Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7na8.cif.gz | 207.1 KB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb7na8.ent.gz | 168.2 KB | Display | PDB format |
PDBx/mmJSON format | 7na8.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7na8_validation.pdf.gz | 942 KB | Display | wwPDB validaton report |
---|---|---|---|---|
Full document | 7na8_full_validation.pdf.gz | 957 KB | Display | |
Data in XML | 7na8_validation.xml.gz | 36.3 KB | Display | |
Data in CIF | 7na8_validation.cif.gz | 55.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/na/7na8 ftp://data.pdbj.org/pub/pdb/validation_reports/na/7na8 | HTTPS FTP |
-Related structure data
Related structure data | 24268MC 7na7C M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-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.) Homo sapiens (human) / Gene: GNAI1 Production host: Insect expression vector pBlueBacmsGCA1His (others) References: UniProt: P63096 |
---|---|
#2: Protein | 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 | 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 |
-Antibody / Protein , 2 types, 2 molecules NR
#4: Antibody | 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 | 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 |
-Non-polymers , 2 types, 2 molecules
#6: Chemical | ChemComp-1KD / |
---|---|
#7: Chemical | ChemComp-CLR / |
-Details
Has ligand of interest | Y |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Complex of GHSR-Gi-ghrelin / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
---|---|
Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
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 |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 82 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: dev_3951: / Classification: refinement | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 283300 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
|