Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.
Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.
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辣椒素结合和 TRPV1 离子通道激活的结构机制
DOI：
10.1038/nchembio.1835
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发表时间：
2015-07
影响因子：
14.8
通讯作者：
Zheng, Jie
中科院分区：
文献类型：
--
作者：
Yang, Fan;Xiao, Xian;Cheng, Wei;Yang, Wei;Yu, Peilin;Song, Zhenzhen;Yarov-Yarovoy, Vladimir;Zheng, Jie
辣椒素通过激活TRPV 1通道赋予辛辣感，具有精致的效力和选择性。辣椒素结合的通道结构以前通过cryo-EM以4.2-4.5 μ m的分辨率解析，但是无法获得机械理解所需的重要细节：辣椒素被注册为小电子密度，既不反映其化学结构，也不反映特定的配体-通道相互作用。我们通过迭代计算获得了缺失的原子级细节，并通过系统的特定站点功能测试进行了确认。我们观察到，结合辣椒素采取“尾朝上，头朝下”的配置。香草基和酰胺基形成特定的相互作用以锚其结合位置，而脂肪族尾部可以采样一系列构象，使其在冷冻EM图像中不可见。辣椒素通过香草基和S4-S5接头之间的“拉接触”相互作用来稳定开放状态。我们的研究提供了辣椒素及其类似物的激动功能的结构机制，并展示了一种有效的方法，以获得原子水平的信息，从冷冻电镜结构。
Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Capsaicin-bound channel structure was previously resolved by cryo-EM at 4.2-to-4.5 Å resolution, however important details required for mechanistic understandings are unavailable: capsaicin was registered as a small electron density, reflecting neither its chemical structure nor specific ligand-channel interactions. We obtained the missing atomic-level details by iterative computation, which were confirmed by systematic site-specific functional tests. We observed that the bound capsaicin takes “tail-up, head-down” configurations. The vanillyl and amide groups form specific interactions to anchor its bound position, while the aliphatic tail may sample a range of conformations, making it invisible in cryo-EM images. Capsaicin stabilizes the open state by “pull-and-contact” interactions between the vanillyl group and the S4-S5 linker. Our study provided a structural mechanism for the agonistic function of capsaicin and its analogs, and demonstrated an effective approach to obtain atomic level information from cryo-EM structures.
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影响因子：
64.5
作者：
CARTER, PJ;WINTER, G;FERSHT, AR
通讯作者：
FERSHT, AR
影响因子：
4.8
作者：
Boukalova, Stepana;Marsakova, Lenka;Vlachova, Viktorie
通讯作者：
Vlachova, Viktorie
影响因子：
56.9
作者：
HIDALGO, P;MACKINNON, R
通讯作者：
MACKINNON, R
影响因子：
6.1
作者：
Kobata, K;Todo, T;Watanabe, T
通讯作者：
Watanabe, T
影响因子：
56.9
作者：
Jensen, Morten O.;Jogini, Vishwanath;Shaw, David E.
通讯作者：
Shaw, David E.