以色列魏兹曼科学研究所Moran Shalev-Benami、以色列希伯来大学Masha Y. Niv和英国伦敦大学玛丽皇后学院Peter J. McCormick合作取得最新进展。他们利用其结构揭示了黑皮质素受体4（MC4R）激活饱合信号的机制。这一研究成果发表在2021年4月15日出版的国际学术期刊《科学》杂志上。

他们介绍了人类MC4R-Gs信号复合物与激动剂setmelanotide（一种最近被批准用于治疗肥胖症的环状肽）结合的冷冻EM结构。这项工作揭示了MC4R激活的机制，强调了启动饱合信号的分子开关。

另外，他们的发现表明，Ca 2+是激动剂所必需的，而不是拮抗剂的功效。这些结果填补了了解MC4R激活的空白，并可能指导未来体重管理药物的设计。

研究人员表示，肥胖在全球盛行，会导致发病率和生活质量下降。MC4R处于食欲、能量稳态和中枢神经系统体重控制的关键，并且是抗肥胖药的主要靶标。

附：英文原文

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

Author: 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

Issue&Volume: 2021/04/15

Abstract: Obesity is a global epidemic causing 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-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 Ca2+ is required for agonist but not antagonist efficacy. These results fill a gap in understanding MC4R activation and could guide the design of future weight management drugs.

DOI: 10.1126/science.abf7958

Source: https://science.sciencemag.org/content/early/2021/04/14/science.abf7958