A Combined Computational and Structural Approach into Understanding the Role of Peptide Binding and Activation of the Melanocortin Receptor 4

The melanocortin receptor 4 (MC4R), is expressed predominantly in the central nervous system and regulates food intake, sexual function and is also thought to be responsible for effects on mood and cognition. It belongs to the melanocortin receptors subfamily of G protein-coupled receptors (GPCRs). Here, we have synthesized and structurally characterized three peptides that bind to MC4R, producing different signaling events. AgRP, a naturally occurring antagonist, HLWNRS, the minimal sequence of the N-terminal with partial agonist activity and aMSH, a full agonistic peptide. By implementing molecular dynamics simulations on the different peptide-receptor complexes, we propose their molecular basis of binding, in order to investigate their differential molecular properties regarding the activation states of the receptor. Our analysis shows that the agonist and partially agonist induce a rotation in transmembrane helix 3, which is known to be involved in the key events occurring during GPCR activation, and ...