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Papers of the Week

Papers: 31 Oct 2020 - 6 Nov 2020

Animal Studies

2020 Nov 02


Editor's Pick

A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.


Liu C, Reese R, Vu S, Rougé L, Shields SD, Kakiuchi-Kiyota S, Chen H, Johnson K, Shi Y P, Chernov-Rogan T, Greiner D M Z, Kohli P B, Hackos D, Brillantes B, Tam C, Li T, Wang J, Safina B, Magnuson S, Volgraf M, et al.
Neuron. 2020 Nov 02.
PMID: 33152265.


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.