+Open data
-Basic information
Entry | Database: PDB / ID: 7f58 | ||||||
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Title | Cryo-EM structure of THIQ-MC4R-Gs_Nb35 complex | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / single particle / Class A G-protein-coupled receptors | ||||||
Function / homology | Function and homology information regulation of eating behavior / melanocyte-stimulating hormone receptor activity / response to melanocyte-stimulating hormone / melanocortin receptor activity / regulation of grooming behavior / energy reserve metabolic process / neuropeptide binding / regulation of metabolic process / feeding behavior / insulin secretion ...regulation of eating behavior / melanocyte-stimulating hormone receptor activity / response to melanocyte-stimulating hormone / melanocortin receptor activity / regulation of grooming behavior / energy reserve metabolic process / neuropeptide binding / regulation of metabolic process / feeding behavior / insulin secretion / positive regulation of bone resorption / negative regulation of feeding behavior / diet induced thermogenesis / peptide hormone binding / Transcriptional and post-translational regulation of MITF-M expression and activity / Peptide ligand-binding receptors / response to insulin / 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 / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / 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 / 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 / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / ubiquitin protein ligase binding / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | ||||||
Authors | Zhang, H. / Chen, L. / Mao, C. / Shen, Q. / Yang, D. / Shen, D. / Qin, J. | ||||||
Citation | Journal: Cell Res / Year: 2021 Title: Structural insights into ligand recognition and activation of the melanocortin-4 receptor. Authors: Huibing Zhang / Li-Nan Chen / Dehua Yang / Chunyou Mao / Qingya Shen / Wenbo Feng / Dan-Dan Shen / Antao Dai / Shanshan Xie / Yan Zhou / Jiao Qin / Jin-Peng Sun / Daniel H Scharf / Tingjun ...Authors: Huibing Zhang / Li-Nan Chen / Dehua Yang / Chunyou Mao / Qingya Shen / Wenbo Feng / Dan-Dan Shen / Antao Dai / Shanshan Xie / Yan Zhou / Jiao Qin / Jin-Peng Sun / Daniel H Scharf / Tingjun Hou / Tianhua Zhou / Ming-Wei Wang / Yan Zhang / Abstract: Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of ...Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric G protein stimulated by the endogenous peptide ligand α-MSH, FDA-approved drugs afamelanotide (Scenesse™) and bremelanotide (Vyleesi™), and a selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and a distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7f58.cif.gz | 199.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7f58.ent.gz | 155.4 KB | Display | PDB format |
PDBx/mmJSON format | 7f58.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7f58_validation.pdf.gz | 934.7 KB | Display | wwPDB validaton report |
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Full document | 7f58_full_validation.pdf.gz | 949.2 KB | Display | |
Data in XML | 7f58_validation.xml.gz | 33.6 KB | Display | |
Data in CIF | 7f58_validation.cif.gz | 50.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/f5/7f58 ftp://data.pdbj.org/pub/pdb/validation_reports/f5/7f58 | HTTPS FTP |
-Related structure data
Related structure data | 31461MC 7f53C 7f54C 7f55C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 3 types, 3 molecules RAN
#1: Protein | Mass: 56053.156 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MC4R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P32245 |
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#2: Protein | Mass: 44284.074 Da / Num. of mol.: 1 Mutation: S54N, G226A, E268A, N271K, K274D, R280K, T284D, I287T Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63092-2 |
#5: Protein | Mass: 13711.284 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli) |
-Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG
#3: Protein | Mass: 41729.582 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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#4: Protein | 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 |
-Non-polymers , 3 types, 9 molecules
#6: Chemical | ChemComp-1I8 / ( |
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#7: Chemical | ChemComp-CA / |
#8: Water | ChemComp-HOH / |
-Details
Has ligand of interest | N |
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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 |
-Sample preparation
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Molecular weight | Value: 0.18 MDa / Experimental value: YES | |||||||||||||||||||||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.5 | |||||||||||||||||||||||||||||||||||||||||||||||||
Specimen | Conc.: 4 mg/ml / 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 |
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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: 62 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.16_3549: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 269832 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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