Structure and selectivity engineering of the M <sub>1</sub> muscarinic receptor toxin complex
Shoji Maeda, Jun Xu, Francois Marie Ngako Kadji, Mary J. Clark, Jiawei Zhao, Naotaka Tsutsumi, Junken Aoki, Roger K. Sunahara, Asuka Inoue, K. Christopher García, Brian K. Kobilka
Abstract
Engineering a toxin Developing drugs that target a specific subtype in a G protein–coupled receptor (GPCR) family is a major challenge. Maeda et al. examined the basis of specificity of a snake venom toxin binding to muscarinic acetylcholine receptors (MAChRs), which mediate many functions of the central and parasympathetic nervous systems. They determined a structure that shows why the mamba venom toxin MT7 is specific for one receptor, M 1 AChR, and also explains how it inhibits downstream signaling. Based on this structure, they engineered MT7 to be selective for another receptor, M 2 AChR, instead of M 1 ChR. The toxin may present a promising scaffold for developing specific GPCR modulators. Science , this issue p. 161