한빛사 논문
Yang Suo1, Zilong Wang2, Lejla Zubcevic1, Allen L. Hsu3, Qianru He2, Mario J. Borgnia1,3, Ru-Rong Ji2, Seok-Yong Lee1,4,*
1 Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA
2 Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, NC 27710, USA
3 Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA
4 Lead Contact
*Corresponding author : Seok-Yong Lee
Abstract
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.
Keywords : Pain; Itch; Sensory neurons; TRPA1; ion channel; cysteine modification; TRP channel; covalent agonist; reactive cysteine; cryo-EM
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