瞬时受体电位通道
化学
电泳剂
神经科学
心理学
生物化学
计算生物学
认知科学
受体
生物
催化作用
作者
Yang Suo,Zilong Wang,Lejla Zubcevic,Allen L. Hsu,Qianru He,Mario J. Borgnia,Ru‐Rong Ji,Seok‐Yong Lee
出处
期刊:Neuron
[Cell Press]
日期:2019-12-19
卷期号:105 (5): 882-894.e5
被引量:118
标识
DOI:10.1016/j.neuron.2019.11.023
摘要
Summary
Transient receptor potential channel subfamily A member 1 (TRPA1) is a Ca2+-permeable cation channel that serves as one of the primary sensors of environmental irritants and noxious substances. Many TRPA1 agonists are electrophiles that are recognized by TRPA1 via covalent bond modifications of specific cysteine residues located in the cytoplasmic domains. However, a mechanistic understanding of electrophile sensing by TRPA1 has been limited due to a lack of high-resolution structural information. Here, we present the cryoelectron microscopy (cryo-EM) structures of nanodisc-reconstituted ligand-free TRPA1 and TRPA1 in complex with the covalent agonists JT010 and BITC at 2.8, 2.9, and 3.1 Å, respectively. Our structural and functional studies provide the molecular basis for electrophile recognition by the extraordinarily reactive C621 in TRPA1 and mechanistic insights into electrophile-dependent conformational changes in TRPA1. This work also provides a platform for future drug development targeting TRPA1.
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