| Literature DB >> 33152265 |
Chang Liu1, Rebecca Reese2, Simon Vu3, Lionel Rougé4, Shannon D Shields2, Satoko Kakiuchi-Kiyota5, Huifen Chen6, Kevin Johnson7, Yu Patrick Shi1, Tania Chernov-Rogan1, Demi Maria Zabala Greiner1, Pawan Bir Kohli1, David Hackos2, Bobby Brillantes8, Christine Tam8, Tianbo Li1, Jianyong Wang1, Brian Safina6, Steve Magnuson6, Matthew Volgraf6, Jian Payandeh4, Jie Zheng3, Alexis Rohou9, Jun Chen10.
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.Entities:
Keywords: TRPA1; biased agonism; covalent; cryo-EM; drug discovery; ion channel; non-covalent; pain
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Year: 2020 PMID： 33152265 PMCID： PMC8244166 DOI： 10.1016/j.neuron.2020.10.014
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 17.173