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

doi:10.1126/science.abf7958

GSTDTAP > 气候变化

DOI	10.1126/science.abf7958
	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
	2021-05-21
发表期刊	Science
出版年	2021
英文摘要	Melanocortin receptor 4 (MC4R) plays a role in regulating food intake: Its activation by a stimulating hormone inhibits appetite, whereas binding to a natural antagonist promotes appetite. Complementing a recent structure of MC4R in an inactive conformation, Israeli et al. present the structure bound to setmelanotide, a weight-control drug, and its G protein–signaling partner (see the Perspective by Farooqi). This work reveals the mechanism of MC4R activation and explains why setmelanotide acts as a potent agonist, whereas a structurally similar compound, SHU9119, is an inhibitor. The structure also provides insight into the contribution of mutations in MCR4 to weight-regulation disorders. Science , abf7958, this issue p. [808][1]; see also abi8942, p. [792][2] 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. [1]: /lookup/doi/10.1126/science.abf7958 [2]: /lookup/doi/10.1126/science.abi8942
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/328820
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Hadar Israeli,Oksana Degtjarik,Fabrizio Fierro,et al. Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling[J]. Science,2021.
APA	Hadar Israeli.,Oksana Degtjarik.,Fabrizio Fierro.,Vidicha Chunilal.,Amandeep Kaur Gill.,...&Moran Shalev-Benami.(2021).Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.Science.
MLA	Hadar Israeli,et al."Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling".Science (2021).