A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.
A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.
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DOI：
10.1016/j.neuron.2020.10.014
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发表时间：
2021-01-20
期刊：
影响因子：
16.2
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Liu C;Reese R;Vu S;Rougé L;Shields SD;Kakiuchi-Kiyota S;Chen H;Johnson K;Shi YP;Chernov-Rogan T;Greiner DMZ;Kohli PB;Hackos D;Brillantes B;Tam C;Li T;Wang J;Safina B;Magnuson S;Volgraf M;Payandeh J;Zheng J;Rohou A;Chen J
TRPA1离子通道通过细胞内半胱氨酸残基的共价修饰被亲电化合物激活。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起相同的生理反应，目前尚不清楚。在这里，我们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袋和配体相互作用机制。与共价激动剂异硫氰酸烯丙酯引起通道脱敏、快速反应和短暂性疼痛不同，GNE551激活TRPA1进入不同的传导状态，而不会脱敏，并诱导持续疼痛。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的偏倚激动作用，这一发现对发现针对不同病因的有效药物具有重要意义。Liu等人确定了非共价激动剂（GNE551）与TRPA1离子通道结合的结构基础。与典型的共价激动剂AITC相比，GNE551激活通道进入不同的导电状态，诱导不同的生理反应，揭示了TRPA1通道的偏向激动作用。
The TRPA1 ion channel is activated by electrophilic compounds through 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 biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies. 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 TRPA1 channel.
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影响因子：
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作者：
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影响因子：
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DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD