ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 11.2 | DOI: 10.1530/ey.18.11.2

Weizmann Institute of Science, Rehovot, Israel.

Science 2021;372(6544): 808–814 doi:

Isreali et al. describe the molecular structure of the melanocortin 4 receptor (MC4R) complexed with its effector G protein (Gs alpha) and setmelanotide, a pharmacological agonist of MC4R.

MC4R is a known key element in body weight regulation, connecting response to leptin with inhibition of hunger and food intake. Targeted deletion of Mc4r in mice induces weight gain (1), and heterozygous loss-of-function mutations in MC4R are frequently found in obese children as well as adults (2, 3). Thus, targeting MC4R pharmacologically is a major focus in the development of weight loss therapies. Setmelanotide is the first US FDA-approved MC4R agonist for treatment of obesity due to genetically based deficiencies of pro-opiomelanocortin (POMC), proprotein subtilisin/kexin type 1 (PCSK1), and leptin receptor LEPR.

The current study contributes important data to our understanding of MC4R signalling. Although a recent publication describes the crystal structure of MC4R bound to an antagonist, and thus provides data about the structure of the inactive receptor (4), the architecture of active MC4R had not been described so far. Using single-particle cryogenic electron microscopy, the authors were able to analyse conformational changes and to display crucial amino acids mediating activation of the receptor. This information may be helpful in modelling of pathogenic MC4R mutations and to identify those patients with MC4R defects that would potentially benefit from setmelanotide treatment.

References: 1. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131-141 (1997).2. Vaisse, C. et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106, 253-262 (2000).3. Farooqi, I. S. et al. Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene. N. Engl. J. Med. 348, 1085-1095 (2003).4. Yu, J. et al. Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding. Science. 368, 428-433 (2020).

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