Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling

Hadar Israeli, Oksana Degtjarik, Fabrizio Fierro, Vidicha Chunilal, Amandeep Kaur Gill, Nicolas J. Roth, Joaquin Botta, Vadivel Prabahar, Yoav Peleg, Li F. Chan, Danny Ben-Zvi, Peter J. McCormick, Masha Y. Niv, Moran Shalev-Benami*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca2+) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs.

Original languageAmerican English
Pages (from-to)808-814
Number of pages7
JournalScience
Volume372
Issue number6544
DOIs
StatePublished - 21 May 2021

Bibliographical note

Funding Information:
This work was funded by the Abisch-Frenkel Foundation and the Minerva Stiftung Foundation (M.S.-B). M.S.-B. holds the Tauro Career Development Chair in Biomedical Research. M.S.-B. is supported by the Zuckerman STEM Leadership Program, the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research, the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly, the Joseph and Wolf Lebovic Lab, the Dov and Ziva Rabinovich Endowed Fund for Structural Biology, the Harmstieg New Scientist Fund, and the Pearl Welinsky Merlo Foundation and by P. and T. Gardner. H.I. is the recipient of a Glassman fellowship. M.Y.N. is supported by Israel Science Foundation (ISF) grant #1129/19. F.F. is the recipient of the S. A. Schonbrunn Fellowship Fund. L.F.C. was supported by a Medical Research Council (MRC) UK/Academy of Medical Sciences Clinician Scientist Grant (G0802796). D.B.-Z. is supported by the Zuckerman STEM Leadership Program. P.J.M. was supported by the BBSRC (BB/R006946/1) and MRC (MR/S008608/1). N.J.R. is funded by an MRC doctoral training partnership, and V.C. is funded by an MRC-Barts Charity iCase award (MRC0227). M.S.-B., M.Y.N., and P.J.M. are members of the EU-funded ERNEST COST action CA18133.

Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved.

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