7AUE

Melanocortin receptor 4 (MC4R) Gs protein complex

Summary for 7AUE

• Entry DOI: 10.2210/pdb7aue/pdb
• EMDB information: 11927
• Descriptor: Melanocortin receptor 4, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (8 entities in total)
• Functional Keywords: mc4r, melanocortin, obesity, gpcr, agonist, setmelanotide, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 157802.70

Authors

Degtjarik, O.,Israeli, H.,Prabahar, V.,Shalev-Benami, M. (deposition date: 2020-11-02, release date: 2021-04-28, Last modification date: 2023-03-15)

Primary citation

Israeli, H.,Degtjarik, O.,Fierro, F.,Chunilal, V.,Gill, A.K.,Roth, N.J.,Botta, J.,Prabahar, V.,Peleg, Y.,Chan, L.F.,Ben-Zvi, D.,McCormick, P.J.,Niv, M.Y.,Shalev-Benami, M.
Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.
Science, 372:808-814, 2021

PubMed 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-G 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 (Ca) 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.

PubMed: 33858992
DOI: 10.1126/science.abf7958

Experimental method

ELECTRON MICROSCOPY (2.97 Å)