Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling
Hadar Israeli, Oksana Degtjarik, Fabrizio Fierro, Vidicha Chunilal, Amandeep Kaur Gill, Nicolas J. Roth, Joaquín Botta, Vadivel Prabahar, Yoav Peleg, Li F. Chan, Danny Ben‐Zvi, Peter J. McCormick, Masha Y. Niv, Moran Shalev-Benami
Abstract
To eat or not to eat Melanocortin receptor 4 (MC4R) plays a role in regulating food intake: Its activation by a stimulating hormone inhibits appetite, whereas binding to a natural antagonist promotes appetite. Complementing a recent structure of MC4R in an inactive conformation, Israeli et al. present the structure bound to setmelanotide, a weight-control drug, and its G protein–signaling partner (see the Perspective by Farooqi). This work reveals the mechanism of MC4R activation and explains why setmelanotide acts as a potent agonist, whereas a structurally similar compound, SHU9119, is an inhibitor. The structure also provides insight into the contribution of mutations in MCR4 to weight-regulation disorders. Science , abf7958, this issue p. 808 ; see also abi8942, p. 792