Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling
Authors: Oksana Degtjarik
Peter J McCormick
Joaquin Botta
Vadivel Prabahar
Fabrizio Fierro
Moran Shalev-Benami
Masha Y Niv
Yoav Peleg
Nicolas J Roth
Li F Chan
Hadar Israeli
Amandeep Kaur Gill
Vidicha Chunilal
Danny Ben-Zvi
Journal: Science (2021)
Discipline: Multidisciplinary
Keywords: Obesity; Melanocortin receptor 4 (MC4R); Cryo-electron microscopy (cryo-EM); Setmelanotide; Agonist
Affiliations: Department of Chemical and Structural Biology, Weizmann
                            Institute of Science, Rehovot 7610001, Israel., Department of Developmental Biology and Cancer Research, The
                            Institute for Medical Research Israel-Canada, The Hebrew
                            University–Hadassah Medical School, Jerusalem, Israel., The Faculty of Agriculture, Food and Environment, The Hebrew
                            University, Rehovot, Israel., The Fritz Haber Center for Molecular Dynamics, The Hebrew
                            University, Jerusalem, Israel., Centre for Endocrinology, William Harvey Research Institute,
                            Barts and the London School of Medicine, Queen Mary, University of
                            London, Charterhouse Square, London, UK., Structural Proteomics Unit (SPU), Life Sciences Core Facilities
                            (LSCF), Weizmann Institute of Science, Rehovot 7610001,
                            Israel.

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. 

Retracted: No

PubPeer comments:
  In contrast, we found that physiological Ca2+ concentrations do not contribute to inverse-agonist activity of SHU9119, nor to AgRP-induced antagonistic activity. Minor correction, but SHU9119 is a neutral antagonist whilst AgRP is the endogenous inverse agonist [Nijenhuis W.A.J., et al., 2001] , 
  MC4R is an unusual GPCR as it has both an endogenous agonist and an endogenous antagonist (14, 15). For other GPCRs, with the exception of the close MC4R homolog MC3R (3), only endogenous agonists have been described. This is incorrect on two counts; firstly AgRP is an inverse agonist, reducing basal activity of MC4R, rather than an antogonist, secondly, GHSR1a (the ghrelin receptor), a GPCR that also exhibits high constiuitive activity, has an endogenous agonist (ghrelin) and an endogenous inverse agonist (LEAP-2). ,