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Yorodumi- PDB-8gy7: Cryo-EM structure of ACTH-bound melanocortin-2 receptor in comple... -
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-Basic information
Entry | Database: PDB / ID: 8gy7 | ||||||
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Title | Cryo-EM structure of ACTH-bound melanocortin-2 receptor in complex with MRAP1 and Gs protein | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / melanocortin-2 receptor / MRAP1 / GPCR / ACTH | ||||||
Function / homology | Function and homology information corticotropin receptor activity / corticotropin hormone receptor binding / type 5 melanocortin receptor binding / Defective ACTH causes obesity and POMCD / type 1 melanocortin receptor binding / type 3 melanocortin receptor binding / type 4 melanocortin receptor binding / melanocortin receptor activity / PKA activation in glucagon signalling / signaling receptor regulator activity ...corticotropin receptor activity / corticotropin hormone receptor binding / type 5 melanocortin receptor binding / Defective ACTH causes obesity and POMCD / type 1 melanocortin receptor binding / type 3 melanocortin receptor binding / type 4 melanocortin receptor binding / melanocortin receptor activity / PKA activation in glucagon signalling / signaling receptor regulator activity / sensory perception of chemical stimulus / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / D1 dopamine receptor binding / negative regulation of adenylate cyclase activity / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / regulation of metabolic process / Hedgehog 'off' state / GTP metabolic process / beta-2 adrenergic receptor binding / G protein-coupled dopamine receptor signaling pathway / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / adenylate cyclase activator activity / positive regulation of macroautophagy / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Adenylate cyclase inhibitory pathway / negative regulation of protein localization to plasma membrane / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / bone development / G-protein beta/gamma-subunit complex binding / Peptide ligand-binding receptors / platelet aggregation / protein localization to plasma membrane / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / electron transport chain / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / hormone activity / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GDP binding / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (12/13) signalling events / extracellular vesicle / positive regulation of cold-induced thermogenesis / 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 / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway Similarity search - Function | ||||||
Biological species | Homo sapiens (human) synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||
Authors | Luo, P. / Feng, W.B. / Ma, S.S. / Dai, A.T. / Yuan, Q.N. / Wu, K. / Yang, D.H. / Wang, M.W. / Xu, H.E. / Jiang, Y. | ||||||
Funding support | China, 1items
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Citation | Journal: Cell Res / Year: 2023 Title: Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1. Authors: Ping Luo / Wenbo Feng / Shanshan Ma / Antao Dai / Kai Wu / Xianyue Chen / Qingning Yuan / Xiaoqing Cai / Dehua Yang / Ming-Wei Wang / H Eric Xu / Yi Jiang / Abstract: G protein-coupled receptors (GPCRs) are regulated by various downstream proteins, of which the melanocortin receptor accessory protein 1 (MRAP1) is closely involved in the regulation of melanocortin ...G protein-coupled receptors (GPCRs) are regulated by various downstream proteins, of which the melanocortin receptor accessory protein 1 (MRAP1) is closely involved in the regulation of melanocortin receptor 2 (MC2R). Assisted by MRAP1, MC2R responds to adrenocorticotropic hormone (ACTH) and stimulates glucocorticoid biogenesis and cortisol secretion. MC2R activation plays an essential role in the hypothalamic-pituitary-adrenal (HPA) axis that regulates stress response, while its dysfunction causes glucocorticoid insufficiency- or cortisol excess-associated disorders. Here, we present a cryo-electron microscopy (cryo-EM) structure of the ACTH-bound MC2R-G-MRAP1 complex. Our structure, together with mutagenesis analysis, reveals a unique sharp kink at the extracellular region of MRAP1 and the 'seat-belt' effect of MRAP1 on stabilizing ACTH binding and MC2R activation. Mechanisms of ACTH recognition by MC2R and receptor activation are also demonstrated. These findings deepen our understanding of GPCR regulation by accessory proteins and provide valuable insights into the ab initio design of therapeutic agents targeting MC2R. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8gy7.cif.gz | 218.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8gy7.ent.gz | 162.1 KB | Display | PDB format |
PDBx/mmJSON format | 8gy7.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8gy7_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 8gy7_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 8gy7_validation.xml.gz | 37.1 KB | Display | |
Data in CIF | 8gy7_validation.cif.gz | 54.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/gy/8gy7 ftp://data.pdbj.org/pub/pdb/validation_reports/gy/8gy7 | HTTPS FTP |
-Related structure data
Related structure data | 34371MC 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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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 41879.465 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI3, GNAS, GNAS1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P08754, UniProt: Q5JWF2 |
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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: Trichoplusia ni (cabbage looper) / References: UniProt: P62873 |
#3: 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: Trichoplusia ni (cabbage looper) / References: UniProt: P59768 |
-Protein , 2 types, 2 molecules PR
#5: Protein | Mass: 20486.178 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MRAP, C21orf61, FALP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8TCY5 |
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#6: Protein | Mass: 67391.219 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: cybC, MC2R, ACTHR / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P0ABE7, UniProt: Q01718 |
-Protein/peptide / Non-polymers , 2 types, 2 molecules M
#4: Protein/peptide | Mass: 2256.655 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: UniProt: P68000 |
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#7: Chemical | ChemComp-CA / |
-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 |
-Sample preparation
Component |
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Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.2 | ||||||||||||||||||||||||||||||||||||||||||||||||
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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.19.2_4158: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59170 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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