Atomistic mechanisms of human TRPA1 activation by electrophile irritants through molecular dynamics simulation and mutual information analysis.

ABSTRACT: The ion channel TRPA1 is a promiscuous chemosensor, with reported response to a wide spectrum of noxious electrophilic irritants, as well as cold, heat, and mechanosensation. It is also implicated in the inception of itch and pain and has hence been investigated as a drug target for novel analgesics. The mechanism of electrophilic activation for TRPA1 is therefore of broad interest. TRPA1 structures with the pore in both open and closed states have recently been published as well as covalent binding modes for electrophile agonists. However, the detailed mechanism of coupling between electrophile binding sites and the pore remains speculative. In addition, while two different cysteine residues (C621 and C665) have been identified as critical for electrophile bonding and activation, the boun

SUBMITTER: Habgood M 

PROVIDER: S-EPMC8943162 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature