7aue | pdb_00007aue
Melanocortin receptor 4 (MC4R) Gs protein complex
Structural highlights
DiseaseMC4R_HUMAN Obesity due to melanocortin 4 receptor deficiency. The disease is caused by mutations affecting the gene represented in this entry. FunctionMC4R_HUMAN Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP).[1] [2] Publication Abstract from PubMedObesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-G(s) signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca(2+)) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs. Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.,Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, Botta J, Prabahar V, Peleg Y, Chan LF, Ben-Zvi D, McCormick PJ, Niv MY, Shalev-Benami M Science. 2021 May 21;372(6544):808-814. doi: 10.1126/science.abf7958. Epub 2021 , Apr 15. PMID:33858992[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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