Department of Biochemical Cellular Pharmacology, Genentech, 103 DNA Way, South San Francisco, CA 94080, USA.
Department of Neuroscience, Genentech, 103 DNA Way, South San Francisco, CA 94080, USA.
Neuron. 2021 Jan 20;109(2):273-284.e4. doi: 10.1016/j.neuron.2020.10.014. Epub 2020 Nov 4.
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.
瞬时受体电位通道 A1（TRPA1）离子通道可被亲电化合物通过细胞内半胱氨酸残基的共价修饰而激活。目前，人们尚不清楚非共价激动剂如何激活该通道，以及共价和非共价激动剂是否会引发相同的生理反应。本研究报告了一种非共价激动剂 GNE551 的发现，并确定了 TRPA1-GNE551 复合物的低温电镜结构，揭示了一个独特的结合口袋和配体相互作用机制。与引发通道脱敏、快速耐受和短暂性疼痛的共价激动剂丙烯基异硫氰酸酯不同，GNE551 将 TRPA1 激活为一种独特的传导状态，不会发生脱敏，并引起持续性疼痛。此外，GNE551 诱发的疼痛对拮抗剂治疗相对不敏感。因此，本研究证明了 TRPA1 的偏性激动作用，这一发现对发现针对不同病因的有效药物具有重要意义。
