Melanocortin-4 receptor (MC4R) is expressed primarily in the hypothalamus and brainstem. It binds to two different neuropeptides, α-melanocyte–stimulating hormone [α-MSH, from proopiomelanocortin (POMC) neurons] and agouti-related protein (AgRP), which exert opposing effects on downstream responses. A crystal structure of MC4R in complex with the cyclic peptide antagonist, SHU9119, revealed a Ca2+-binding site that influences downstream signaling.