Structure and selectivity engineering of the M<sub>1</sub> muscarinic receptor toxin complex

doi:10.1126/science.aax2517

GSTDTAP > 气候变化

DOI	10.1126/science.aax2517
	Structure and selectivity engineering of the M₁ muscarinic receptor toxin complex
	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
	2020-07-10
发表期刊	Science
出版年	2020
英文摘要	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, M1AChR, and also explains how it inhibits downstream signaling. Based on this structure, they engineered MT7 to be selective for another receptor, M2AChR, instead of M1ChR. The toxin may present a promising scaffold for developing specific GPCR modulators. Science , this issue p. [161][1] 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. [1]: /lookup/doi/10.1126/science.aax2517
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/283396
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Shoji Maeda,Jun Xu,Francois Marie N. Kadji,et al. Structure and selectivity engineering of the M₁ muscarinic receptor toxin complex[J]. Science,2020.
APA	Shoji Maeda.,Jun Xu.,Francois Marie N. Kadji.,Mary J. Clark.,Jiawei Zhao.,...&Brian K. Kobilka.(2020).Structure and selectivity engineering of the M₁ muscarinic receptor toxin complex.Science.
MLA	Shoji Maeda,et al."Structure and selectivity engineering of the M₁ muscarinic receptor toxin complex".Science (2020).