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

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.