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Chernov-Rogan T , Gianti E , Liu C , Villemure E , Cridland AP , Hu X , Ballini E , Lange W , Deisemann H , Li T , Ward SI , Hackos DH , Magnuson S , Safina B , Klein ML , Volgraf M , Carnevale V , Chen J
TRPA1 modulation by piperidine carboxamides suggests an evolutionarily conserved binding site and gating mechanism
Proc Natl Acad Sci U S A. 2019 Dec 17;116(51) :26008-26019
PMID: 31796582    PMCID: PMC6926016   
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The transient receptor potential ankyrin 1 (TRPA1) channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. As a ligand-gated channel, TRPA1 can be activated by electrophilic compounds such as allyl isothiocyanate (AITC) through covalent modification or activated by noncovalent agonists through ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we report a class of piperidine carboxamides (PIPCs) as potent, noncovalent agonists of human TRPA1. Based on their species-specific effects on human and rat channels, we identified residues critical for channel activation; we then generated binding modes for TRPA1-PIPC interactions using structural modeling, molecular docking, and mutational analysis. We show that PIPCs bind to a hydrophobic site located at the interface of the pore helix 1 (PH1) and S5 and S6 transmembrane segments. Interestingly, this binding site overlaps with that of known allosteric modulators, such as A-967079 and propofol. Similar binding sites, involving pi-helix rearrangements on S6, have been recently reported for other TRP channels, suggesting an evolutionarily conserved mechanism. Finally, we show that for PIPC analogs, predictions from computational modeling are consistent with experimental structure-activity studies, thereby suggesting strategies for rational drug design.
1091-6490 Chernov-Rogan, Tania Gianti, Eleonora Liu, Chang Villemure, Elisia Cridland, Andrew P Hu, Xiaoyu Ballini, Elisa Lange, Wienke Deisemann, Heike Li, Tianbo Ward, Stuart I Hackos, David H Magnuson, Steven Safina, Brian Klein, Michael L Volgraf, Matthew Carnevale, Vincenzo ORCID: http://orcid.org/0000-0002-1918-8280 Chen, Jun R01 GM093290/GM/NIGMS NIH HHS/United States S10 OD020095/OD/NIH HHS/United States Journal Article United States Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):26008-26019. doi: 10.1073/pnas.1913929116. Epub 2019 Dec 3.