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Yorodumi- EMDB-34371: Cryo-EM structure of ACTH-bound melanocortin-2 receptor in comple... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-34371 | |||||||||
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Title | Cryo-EM structure of ACTH-bound melanocortin-2 receptor in complex with MRAP1 and Gs protein | |||||||||
Map data | ||||||||||
Sample |
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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 / signaling receptor regulator activity / sensory perception of chemical stimulus ...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 / signaling receptor regulator activity / sensory perception of chemical stimulus / 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 / GTP metabolic process / negative regulation of protein localization to plasma membrane / G protein-coupled dopamine receptor signaling pathway / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / PKA activation in glucagon signalling / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of macroautophagy / mu-type opioid receptor binding / developmental growth / corticotropin-releasing hormone receptor 1 binding / D1 dopamine receptor binding / Adenylate cyclase inhibitory pathway / Hedgehog 'off' state / beta-2 adrenergic receptor binding / adenylate cyclase activator activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / protein localization to plasma membrane / G protein-coupled receptor binding / G protein-coupled receptor activity / electron transport chain / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / 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 activation / hormone activity / G protein-coupled acetylcholine receptor signaling pathway / 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 / platelet aggregation / 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 / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / periplasmic space / electron transfer activity / cell cycle / iron ion binding / G protein-coupled receptor signaling pathway Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / synthetic construct (others) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Luo P / Feng WB / Ma SS / Dai AT / Yuan QN / Wu K / Yang DH / Wang MW / Xu HE / Jiang Y | |||||||||
Funding support | China, 1 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_34371.map.gz | 47 MB | EMDB map data format | |
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Header (meta data) | emd-34371-v30.xml emd-34371.xml | 23.5 KB 23.5 KB | Display Display | EMDB header |
Images | emd_34371.png | 40.7 KB | ||
Others | emd_34371_half_map_1.map.gz emd_34371_half_map_2.map.gz | 40.8 MB 40.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-34371 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-34371 | HTTPS FTP |
-Validation report
Summary document | emd_34371_validation.pdf.gz | 603.2 KB | Display | EMDB validaton report |
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Full document | emd_34371_full_validation.pdf.gz | 602.8 KB | Display | |
Data in XML | emd_34371_validation.xml.gz | 11.4 KB | Display | |
Data in CIF | emd_34371_validation.cif.gz | 13.1 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34371 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34371 | HTTPS FTP |
-Related structure data
Related structure data | 8gy7MC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_34371.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.04 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_34371_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_34371_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : ACTH-bound melanocortin-2 receptor in complex with MRAP1 and Gs p...
+Supramolecule #1: ACTH-bound melanocortin-2 receptor in complex with MRAP1 and Gs p...
+Supramolecule #2: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Supramolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Supramolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Supramolecule #5: ACTH
+Supramolecule #6: MRAP1
+Supramolecule #7: melanocortin-2 receptor
+Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-3,Guanine n...
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: Corticotropin
+Macromolecule #5: Melanocortin-2 receptor accessory protein
+Macromolecule #6: Soluble cytochrome b562,Adrenocorticotropic hormone receptor,mela...
+Macromolecule #7: CALCIUM ION
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.2 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 59170 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |