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

  • Science. 2021 May 21;372(6544):808-814. doi: 10.1126/science.abf7958.
Hadar Israeli  #  1  2 ,  Oksana Degtjarik  #  1 ,  Fabrizio Fierro  3  4 ,  Vidicha Chunilal  5 ,  Amandeep Kaur Gill  5 ,  Nicolas J Roth  5 ,  Joaquin Botta  5 ,  Vadivel Prabahar  1 ,  Yoav Peleg  6 ,  Li F Chan  5 ,  Danny Ben-Zvi  7 ,  Peter J McCormick  8 ,  Masha Y Niv  9  4 ,  Moran Shalev-Benami  10
Affiliations
  • 1. Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 2. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • 3. The Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel.
  • 4. The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem, Israel.
  • 5. Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary, University of London, Charterhouse Square, London, UK.
  • 6. Structural Proteomics Unit (SPU), Life Sciences Core Facilities (LSCF), Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 7. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel. [email protected] [email protected] [email protected] [email protected].
  • 8. Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary, University of London, Charterhouse Square, London, UK. [email protected] [email protected] [email protected] [email protected].
  • 9. The Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel. [email protected] [email protected] [email protected] [email protected].
  • 10. Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. [email protected] [email protected] [email protected] [email protected].
  • # Contributed equally.
PMID: 33858992 DOI: 10.1126/science.abf7958
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.