Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers.
Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in gingers.
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生姜中的刺激性化合物激活 TRPV1 通道的结构机制。
DOI：
10.1111/bph.14766
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发表时间：
2019
影响因子：
7.3
通讯作者：
Zheng,Jie
中科院分区：
文献类型：
--
作者：
Yin,Yue;Dong,Yawen;Vu,Simon;Yang,Fan;Yarov-Yarovoy,Vladimir;Tian,Yuhua;Zheng,Jie
背景与目的生姜与辣椒一样，通过一组香草素类化合物激活伤害性瞬时受体电位香草素1（TRPV 1）离子通道产生刺激性刺激。这些化合物如何与TRPV 1相互作用尚不清楚。实验方法我们使用计算结构建模，功能测试（电生理学和钙成像）和诱变来研究配体-通道相互作用的结构机制。Key ResultsThe potential of three principal pungent compounds from ginger -姜烯酚，姜酚，和姜酮-依赖于TRPV 1通道中与辣椒辛辣化合物辣椒素形成氢键的相同的两个残基。计算模型揭示了这些生姜化合物的结合姿势与辣椒素的结合姿势相似，包括“头朝下尾朝上”的取向，两个特定的氢键，以及脂肪族尾部的货车德瓦尔斯相互作用的重要贡献。我们的研究还确定了姜酮的一种新的水平结合姿势，使其在结合在配体结合口袋内时能够直接与通道孔相互作用。这些意见提供了一个分子水平的解释如何独特的结构在生姜化合物影响其通道激活potential.Conclusions和ImplicationsMechanism的见解姜化合物和TRPV 1阳离子通道的相互作用，应有助于指导药物发现的努力，以调节伤害性感受。
Background and PurposeLike chili peppers, gingers produce pungent stimuli by a group of vanilloid compounds that activate the nociceptive transient receptor potential vanilloid 1 (TRPV1) ion channel. How these compounds interact with TRPV1 remains unclear.Experimental ApproachWe used computational structural modelling, functional tests (electrophysiology and calcium imaging), and mutagenesis to investigate the structural mechanisms underlying ligand–channel interactions.Key ResultsThe potency of three principal pungent compounds from ginger —shogaol, gingerol, and zingerone—depends on the same two residues in the TRPV1 channel that form a hydrogen bond with the chili pepper pungent compound, capsaicin. Computational modelling revealed binding poses of these ginger compounds similar to those of capsaicin, including a “head‐down tail‐up” orientation, two specific hydrogen bonds, and important contributions of van der Waals interactions by the aliphatic tail. Our study also identified a novel horizontal binding pose of zingerone that allows it to directly interact with the channel pore when bound inside the ligand‐binding pocket. These observations offer a molecular level explanation for how unique structures in the ginger compounds affect their channel activation potency.Conclusions and ImplicationsMechanistic insights into the interactions of ginger compounds and the TRPV1 cation channel should help guide drug discovery efforts to modulate nociception.