小柯机器人

美国斯坦福大学医学院Brian K. Kobilka和Shoji Maeda研究组合作取得最新进展。他们完成了M1毒蕈碱受体毒素复合物的结构和选择性工程化。这一研究成果于2020年7月10日发表在《科学》杂志上。

他们介绍了与MT7（一种亚型选择性抗M1AChR蛇毒毒素）形成复合物的M1AChR的晶体结构。该结构揭示了MT7对M1AChR的极端亚型特异性的分子基础，以及其调节受体功能的机制。通过结构指导的MT7手指区域的体外工程设计，他们已经将选择性从M1AChR转换为M2AChR，表明三指折叠是开发G蛋白偶联受体调节子的有望支架。

研究人员表示，毒蕈碱毒素（MTs）是曼巴蛇产生的天然毒素，主要与毒蕈碱型乙酰胆碱受体（MAChRs）结合并调节其功能。尽管它们的一级和三级结构相似，但MT对不同的MAChRs表现出不同的结合选择性。关于MT如何区分MAChR的分子细节尚不清楚。

附：英文原文

Title: Structure and selectivity engineering of the M1 muscarinic receptor toxin complex

Author: Shoji Maeda, Jun Xu, Francois Marie N. Kadji, Mary J. Clark, Jiawei Zhao, Naotaka Tsutsumi, Junken Aoki, Roger K. Sunahara, Asuka Inoue, K. Christopher Garcia, Brian K. Kobilka

Issue&Volume: 2020/07/10

Abstract: Muscarinic toxins (MTs) are natural toxins produced by mamba snakes that primarily bind to muscarinic acetylcholine receptors (MAChRs) and modulate their function. Despite their similar primary and tertiary structures, MTs show distinct binding selectivity toward different MAChRs. The molecular details of how MTs distinguish MAChRs are not well understood. Here, we present the crystal structure of M1AChR in complex with MT7, a subtype-selective anti-M1AChR snake venom toxin. The structure reveals the molecular basis of the extreme subtype specificity of MT7 for M1AChR and the mechanism by which it regulates receptor function. Through in vitro engineering of MT7 finger regions that was guided by the structure, we have converted the selectivity from M1AChR toward M2AChR, suggesting that the three-finger fold is a promising scaffold for developing G protein–coupled receptor modulators.

DOI: 10.1126/science.aax2517

Source: https://science.sciencemag.org/content/369/6500/161