Determination of the melanocortin-4 receptor structure identifies Ca <sup>2+</sup> as a cofactor for ligand binding
Jing Yu, Luis E. Gimenez, Ciria C. Hernández, Yiran Wu, Ariel H. Wein, Gye Won Han, Kyle M. McClary, Sanraj R. Mittal, Kylie Burdsall, Benjamin Stauch, Lijie Wu, Sophia N. Stevens, Alys Peisley, Savannah Y. Williams, Valerie Chen, Glenn L. Millhauser, Suwen Zhao, Roger D. Cone, Raymond C. Stevens
Abstract
Some calcium is required for binding The melanocortin-4 receptor (MC4R) coordinates food intake and energy expenditure and is a target for treating obesity. MC4R is an unusual G protein–coupled receptor, in part because it binds either an endogenous agonist or an endogenous antagonist, leading to reduced appetite or increased food intake, respectively. Yu et al. determined the structure of MC4R bound to an antagonist (see the Perspective by Chaturvedi and Shukla). This structure revealed a calcium ion coordinated by the receptor and the antagonist. Biochemical studies showed that the calcium ion also increased the affinity for endogenous agonist, which translated into increased potency. The authors also confirm a previous finding that MC4R directly couples to the ion channel Kir7.1 and regulates channel gating. Science , this issue p. 428 ; see also p. 369