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

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. •GNE551-TRPA1 co-structure reveals an agonist transmembrane binding pocket•Unlike AITC, GNE551 activates TRPA1 without channel desensitization•GNE551 induces persistent pain, whereas AITC induces transient pain•GNE551-evoked pain is less sensitive to TRPA1 antagonists Liu et al. determine the structural basis for the binding of a non-covalent agonist (GNE551) to the TRPA1 ion channel. Compared to the canonical covalent agonist AITC, GNE551 activates channels into distinct conducting states and induces different physiological responses, revealing a biased agonism of the TRPA1 channel.