Monogenic obesity caused by mutations in the melanocortin-4 receptor (MC4R) gene remains a significant health challenge, despite numerous efforts to discover effective treatments. The MC4R has emerged Show more
Monogenic obesity caused by mutations in the melanocortin-4 receptor (MC4R) gene remains a significant health challenge, despite numerous efforts to discover effective treatments. The MC4R has emerged as a promising target for drug development due to its role in energy homeostasis and adipose tissue formation. Show less
Melanocortin receptor 4 (MC4R) is expressed predominantly in the central nervous system and regulates food intake and sexual function and is also thought to be responsible for effects on mood and cogn Show more
Melanocortin receptor 4 (MC4R) is expressed predominantly in the central nervous system and regulates food intake and sexual function and is also thought to be responsible for effects on mood and cognition. It belongs to the melanocortin receptor 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 is a naturally occurring antagonist, HLWNRS is the minimal sequence of the N-terminal with partial agonist activity, and aMSH is a full agonistic peptide. By implementing molecular dynamics simulations on the different peptide-receptor complexes, we propose their molecular basis of binding to investigate their differential molecular properties regarding the activation states of the receptor. Our analysis shows that the agonist and partial agonist may induce rotation in transmembrane helix 3, which is known to be involved in the key events occurring during GPCR activation, and this movement is impacted by certain aromatic residues and their positioning in the orthosteric binding site of the receptor. Show less
Innovative crystallographic techniques have resulted in an exponential growth in the number of solved G-protein coupled receptor (GPCR) structures and a better understanding of the mechanisms of class Show more
Innovative crystallographic techniques have resulted in an exponential growth in the number of solved G-protein coupled receptor (GPCR) structures and a better understanding of the mechanisms of class A receptor activation and G protein binding. The recent release of the type 1 receptor for the corticotropin-releasing factor and the glucagon receptor structures, two members of the secretin-like family, gives the opportunity to understand these mechanisms of activation in this family of GPCRs. Here, we addressed the comparison of the functional elements of class A and secretin-like GPCRs, using the glucose-dependent insulinotropic polypeptide receptor (GIPR) as a model receptor. Inactive and active models of GIPR permitted to select, by structural homology with class A GPCRs, several residues that may form key interactions presumably involved in receptor activation and Gs coupling, for pharmacological evaluation. Mutants on these amino acids were expressed in HEKT 293 cells and characterized in terms of GIP-induced cAMP production. We identified various functional domains spanning from the peptide-binding to the G protein pockets: including: a network linking the extracellular part of transmembrane (TM) 6 with TMs 2 and 7; a polar lock that resembles the ionic-lock in class A GPCRs; an interaction between TMs 3 and 7 that favors activation; and two clusters of polar/charged and of hydrophobic residues that interact with the C-terminus of the Gα. The results show that despite the low degree of sequence similarity between rhodopsin- and secretin-like GPCRs, the two families share conserved elements in their mechanisms of activation and G protein binding. Show less