TRPA1 modulation by piperidine carboxamides suggests an evolutionarily conserved binding site and gating mechanism
Abstract
The TRPA1 channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. TRPA1 can be activated by electrophilic compounds via covalent modification or activated by noncovalent agonists via ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we identified a group of noncovalent agonists and used them to explore TRPA1 gating through iterative functional analyses, molecular modeling, and structure–activity relationship studies. We show that TRPA1 possesses an evolutionarily conserved ligand binding site common to other TRP channels. The combination of computational modeling and experimental structure–activity data lays the foundations for rational drug design.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 03, 2019
- Source ID
- 10.1073/pnas.1913929116
Entities
People
- Andrew P. Cridland
- Brian Safina
- Chang Liu
- David H. Hackos
- Eleonora Gianti
- Elisa Ballini
- Elisia Villemure
- Heike Deisemann
- Jun Chen
- Matthew Volgraf
- Michael L. Klein
- Steven Magnuson
- Stuart I. Ward
- Tania Chernov-rogan
- Tianbo Li
- Vincenzo Carnevale
- Wienke Lange
- Xiaoyu Hu
Organizations
- Genentech
- National Institute of General Medical Sciences
- National Science Foundation
- Temple University
- United States Army Research Laboratory