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Crystal structure of the Melanocortin-4 Receptor (MC4R) in complex with S25
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 PubMedMelanocortin 4 receptor (MC4-R) antagonists are actively sought for treating cancer cachexia. We determined the structures of complexes with PG-934 and SBL-MC-31. These peptides differ from SHU9119 by substituting His(6) with Pro(6) and inserting Gly(10) or Arg(10). The structures revealed two subpockets at the TM7-TM1-TM2 domains, separated by N285(7.36). Two peptide series based on the complexed peptides led to an antagonist activity and selectivity SAR study. Most ligands retained the SHU9119 potency, but several SBL-MC-31-derived peptides significantly enhanced MC4-R selectivity over MC1-R by 60- to 132-fold. We also investigated MC4-R coupling to the K(+) channel, Kir7.1. Some peptides activated the channel, whereas others induced channel closure independently of G protein coupling. In cell culture studies, channel activation correlated with increased feeding, while a peptide with Kir7.1 inhibitory activity reduced eating. These results highlight the potential for targeting the MC4-R:Kir7.1 complex for treating positive and restrictive eating disorders. Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design.,Gimenez LE, Martin C, Yu J, Hollanders C, Hernandez CC, Wu Y, Yao D, Han GW, Dahir NS, Wu L, Van der Poorten O, Lamouroux A, Mannes M, Zhao S, Tourwe D, Stevens RC, Cone RD, Ballet S J Med Chem. 2024 Feb 22;67(4):2690-2711. doi: 10.1021/acs.jmedchem.3c01822. Epub , 2024 Feb 12. PMID:38345933[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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