Human TRPV1 structure and inhibition by the analgesic SB-366791.
Human TRPV1 structure and inhibition by the analgesic SB-366791.
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DOI：
10.1038/s41467-023-38162-9
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发表时间：
2023-04-28
影响因子：
16.6
通讯作者：
Sobolevsky, Alexander I.
中科院分区：
文献类型：
--
作者：
Neuberger, Arthur;Oda, Mai;Nikolaev, Yury A.;Nadezhdin, Kirill D.;Gracheva, Elena O.;Bagriantsev, Sviatoslav N.;Sobolevsky, Alexander I.
自阿片类药物危机以来，疼痛治疗在概念上一直停滞不前，这突出了用阿片类药物治疗疼痛的危险。传统的基于止痛剂的治疗的另一种无成瘾策略是靶向疼痛通路起源处的受体，例如瞬时受体电位（TRP）离子通道。因此，TRP通道的香草素亚家族的创始成员TRPV 1代表了最受欢迎的疼痛治疗靶点之一。对选择性TRPV 1抑制剂的需求不仅限于疼痛治疗，还包括与该通道相关的其他疾病，包括精神疾病。在这里，我们报告的冷冻电子显微镜结构的人TRPV 1在载脂蛋白状态和复杂的TRPV 1特异性纳摩尔亲和力镇痛拮抗剂SB-366791。SB-366791与香草素位点结合，并作为变构hTRPV 1抑制剂发挥作用。SB-366791结合位点得到诱变结合电生理记录的支持，可以进一步探索以设计在疾病条件下靶向TRPV 1的新药。靶向瞬时受体电位（TRP）通道的小分子可用于控制疼痛。在这里，Neuberger等人报告了在不添加配体或存在TRPV 1特异性拮抗剂SB-366791的情况下人TRPV 1的冷冻EM结构，为设计新的有前途的镇痛剂提供了见解。
Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions. Small molecules targeting transient receptor potential (TRP) channels might be used to control pain. Here, Neuberger et al. report cryo-EM structures of human TRPV1 in the absence of added ligands or in the presence of the TRPV1-specific antagonist SB-366791, providing insights for the design of new promising analgesics.
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影响因子：
64.8
作者：
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通讯作者：
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影响因子：
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作者：
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--
依赖香草素的TRPV1从冷冻集合分析中开放轨迹。
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
64.5
作者：
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通讯作者：
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