@article{a89dbd4a604f4150af703c2659b718eb,
title = "A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel",
abstract = "The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.",
keywords = "biased agonism, covalent, cryo-EM, drug discovery, ion channel, non-covalent, pain, TRPA1",
author = "Chang Liu and Rebecca Reese and Simon Vu and Lionel Roug{\'e} and Shields, {Shannon D.} and Satoko Kakiuchi-Kiyota and Huifen Chen and Kevin Johnson and Shi, {Yu Patrick} and Tania Chernov-Rogan and Greiner, {Demi Maria Zabala} and Kohli, {Pawan Bir} and David Hackos and Bobby Brillantes and Christine Tam and Tianbo Li and Jianyong Wang and Brian Safina and Steve Magnuson and Matthew Volgraf and Jian Payandeh and Jie Zheng and Alexis Rohou and Jun Chen",
note = "Funding Information: We would like to thank Kevin Ford, Michelle Dourado, Gloria Granados, and colleagues at BioMolecular Resources in Genentech for their assistance. We would also like to thank Craig Yoshioka (OHSU) for collecting the cryo-EM images and Dr. Michael Sanguinetti for his critical reading of the manuscript. The research is supported by Genentech and by the National Institute of Health (grant no. NS103954 to J.Z.). A portion of this research was supported by NIH grant no. U24GM129547 and performed at the PNCC in OHSU through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. ",
year = "2020",
doi = "10.1016/j.neuron.2020.10.014",
language = "English (US)",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
}