MC4R biased signalling and the conformational basis of biological function selections

• Published in: Journal of cellular and molecular medicine Vol. 26; no. 15; pp. 4125 - 4136
• Main Authors: Liu, Zekun, Hruby, Victor J.
• Format: Journal Article
• Language: English
• Published: Chichester John Wiley & Sons, Inc 01.08.2022; John Wiley and Sons Inc
• Subjects: Agonists; Appetite; Biased signalling; Blood pressure; Conformational studies; Drug development; Evolution; G protein-coupled receptors; Heart rate; Homeostasis; Hypothalamus; Ligands; MC4R; MC4R drug design; MC4R structure; Melanocortin; Melanocortin MC4 receptors; Mutation; Neurons; Obesity; Peptides; Proteins; Review; Reviews; Signal transduction; Weight control
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.17441

The MC4R, a GPCR, has long been a major target for obesity treatment. As the most well‐studied melanocortin receptor subtype, the evolutionary knowledge pushes the drug development and structure–activity relationship (SAR) moving forward. The past decades have witnessed the evolution of scientists' view on GPCRs gradually from the control of a single canonical signalling pathway via a bilateral ‘active‐inactive’ model to a multi‐state alternative model where the ligands' binding affects the selection of the downstream signalling. This evolution brings the concept of biased signalling and the beginning of the next generation of peptide drug development, with the aim of turning from receptor subtype specificity to signalling pathway selectivity. The determination of the value structures of the MC4R revealed insights into the working mechanism of MC4R activation upon binding of agonists. However, new challenge has risen as we seek to unravel the mystery of MC4R signalling selection. Thus, more biased agonists and ligands with representative biological functions are needed to solve the rest of the puzzle.