Journal
SCIENCE
Volume 372, Issue 6544, Pages 808-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abf7958
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Funding
- Abisch-Frenkel Foundation
- Minerva Stiftung Foundation
- Zuckerman STEM Leadership Program
- Ilse Katz Institute for Material Sciences and Magnetic Resonance Research
- Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly
- Joseph and Wolf Lebovic Lab
- Dov and Ziva Rabinovich Endowed Fund for Structural Biology
- Harmstieg New Scientist Fund
- Pearl Welinsky Merlo Foundation
- Glassman fellowship
- Israel Science Foundation (ISF) [1129/19]
- S. A. Schonbrunn Fellowship Fund
- Medical Research Council (MRC) UK/Academy of Medical Sciences Clinician Scientist Grant [G0802796]
- BBSRC [BB/R006946/1]
- MRC [MR/S008608/1]
- MRC doctoral training partnership
- MRC-Barts Charity iCase award [MRC0227]
- [CA18133]
- BBSRC [BB/R006946/1] Funding Source: UKRI
- MRC [MR/S008608/1] Funding Source: UKRI
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This study elucidated the mechanism of MC4R activation, identified a molecular switch for initiating satiation signaling, and suggested the involvement of calcium in agonist efficacy. These findings may guide the design of future weight-management drugs.
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.
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