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.

TRPA1 离子通道被亲电子化合物通过细胞内半胱氨酸残基的共价修饰激活。非共价激动剂如何激活通道以及共价和非共价激动剂是否引发相同的生理反应尚不清楚。在这里，我们报告了非共价激动剂 GNE551 的发现，并确定了 TRPA1-GNE551 复合物的低温电镜结构，揭示了独特的结合袋和配体相互作用机制。与引起通道脱敏、快速反应和短暂性疼痛的共价激动剂异硫氰酸烯丙酯不同，GNE551 将 TRPA1 激活到一种独特的导电状态，而不会脱敏并诱导持续性疼痛。此外，GNE551 诱发的疼痛对拮抗剂治疗相对不敏感。因此，我们证明了 TRPA1 的偏激激动，