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Yorodumi- PDB-8ioc: Cryo-EM structure of the gamma-MSH-bound human melanocortin recep... -
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-Basic information
Entry | Database: PDB / ID: 8ioc | ||||||||||||||||||||||||||||||||||||
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Title | Cryo-EM structure of the gamma-MSH-bound human melanocortin receptor 3 (MC3R)-Gs complex | ||||||||||||||||||||||||||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / human melanocortin receptor 3 / G protein-coupled receptor / ligand recpgnition | ||||||||||||||||||||||||||||||||||||
Function / homology | Function and homology information homoiothermy / melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / sodium ion homeostasis / regulation of feeding behavior / neuropeptide binding / regulation of metabolic process / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma ...homoiothermy / melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / sodium ion homeostasis / regulation of feeding behavior / neuropeptide binding / regulation of metabolic process / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / locomotor rhythm / peptide hormone binding / PKA activation in glucagon signalling / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / intracellular transport / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / Hedgehog 'off' state / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase activator activity / regulation of heart rate / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / viral budding from plasma membrane / trans-Golgi network membrane / Regulation of insulin secretion / G protein-coupled receptor binding / circadian regulation of gene expression / G-protein beta/gamma-subunit complex binding / bone development / 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 / cognition / platelet aggregation / 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 / regulation of blood pressure / 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 Similarity search - Function | ||||||||||||||||||||||||||||||||||||
Biological species | Homo sapiens (human) Influenza A virus Bos taurus (cattle) synthetic construct (others) | ||||||||||||||||||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.86 Å | ||||||||||||||||||||||||||||||||||||
Authors | Feng, W.B. / Zhou, Q.T. / Chen, X.Y. / Dai, A.T. / Cai, X.Q. / Liu, X. / Zhao, F.H. / Chen, Y. / Ye, C.Y. / Xu, Y.N. ...Feng, W.B. / Zhou, Q.T. / Chen, X.Y. / Dai, A.T. / Cai, X.Q. / Liu, X. / Zhao, F.H. / Chen, Y. / Ye, C.Y. / Xu, Y.N. / Cong, Z.T. / Li, H. / Lin, S. | ||||||||||||||||||||||||||||||||||||
Funding support | China, 11items
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Citation | Journal: Cell Discov / Year: 2023 Title: Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors. Authors: Wenbo Feng / Qingtong Zhou / Xianyue Chen / Antao Dai / Xiaoqing Cai / Xiao Liu / Fenghui Zhao / Yan Chen / Chenyu Ye / Yingna Xu / Zhaotong Cong / Hao Li / Shi Lin / Dehua Yang / Ming-Wei Wang / Abstract: Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin ...Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin pigmentation through five MCR subtypes (MC1R-MC5R). The structural basis of subtype selectivity of the endogenous agonist γ-MSH and non-selectivity of agonist α-MSH remains elusive, as the two agonists are highly similar with a conserved HFRW motif. Here, we report three cryo-electron microscopy structures of MC3R-G in complex with γ-MSH and MC5R-G in the presence of α-MSH or a potent synthetic agonist PG-901. The structures reveal that α-MSH and γ-MSH adopt a "U-shape" conformation, penetrate into the wide-open orthosteric pocket and form massive common contacts with MCRs via the HFRW motif. The C-terminus of γ-MSH occupies an MC3R-specific complementary binding groove likely conferring subtype selectivity, whereas that of α-MSH distances itself from the receptor with neglectable contacts. PG-901 achieves the same potency as α-MSH with a shorter length by rebalancing the recognition site and mimicking the intra-peptide salt bridge in α-MSH by cyclization. Solid density confirmed the calcium ion binding in MC3R and MC5R, and the distinct modulation effects of divalent ions were demonstrated. Our results provide insights into ligand recognition and subtype selectivity among MCRs, and expand the knowledge of signal transduction among MCR family members. | ||||||||||||||||||||||||||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8ioc.cif.gz | 204.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8ioc.ent.gz | 154.5 KB | Display | PDB format |
PDBx/mmJSON format | 8ioc.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/io/8ioc ftp://data.pdbj.org/pub/pdb/validation_reports/io/8ioc | HTTPS FTP |
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-Related structure data
Related structure data | 35615MC 8inrC 8iodC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 41879.465 Da / Num. of mol.: 1 Mutation: G49D,E50N,L63Y,ten mutations and A249D,S252D,L272D,I372A,V375I,G226A,A366S Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1, GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096, UniProt: P63092 |
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#2: Protein | Mass: 40226.992 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 |
#4: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212 |
-Protein / Protein/peptide / Antibody / Non-polymers , 4 types, 4 molecules RLN
#3: Protein | Mass: 56351.914 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Influenza A virus (strain A/Victoria/3/1975 H3N2), (gene. exp.) Homo sapiens (human) Gene: HA, MC3R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P03435, UniProt: P41968 |
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#5: Protein/peptide | Mass: 1516.747 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) |
#6: Antibody | Mass: 17352.498 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) |
#7: Chemical | ChemComp-CA / |
-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
Component | Name: Cryo-EM structure of gamma-MSH-bound human melanocortin receptor 3 in complex with G protein Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.4 |
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 |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: NONE | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1102647 / Symmetry type: POINT | ||||||||||||||||||||||||
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