Tamoxifen complexes with the voltage-gated sodium channel reveal novel drug binding sites
Tamoxifen complexes with the voltage-gated sodium channel reveal novel drug binding sites
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他莫昔芬与电压门控钠通道的复合物揭示了新的药物结合位点
DOI：
10.1016/j.bpj.2021.11.2583
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发表时间：
2022
影响因子：
3.4
通讯作者：
Hollingworth D
中科院分区：
文献类型：
--
作者：
Hollingworth D
在旨在鉴定与电压门控钠通道（VGSC）相互作用的新型化合物的研究中，为了潜在开发用于治疗通道病的新药，他莫昔芬（一种广泛用于乳腺癌治疗和预防的药物）显示出以高亲和力特异性结合NavMs钠通道。我们的晶体学研究表明，他莫昔芬结合到一个迄今为止未确定的结合位点在这个通道的方式承担类似于其结合到其靶雌激素受体。对天然和突变通道的电生理学研究（苏拉，Hollingworth，Ng，Lamore，DeCaen，Wallace，Molecular Cell，2021）表明，他莫昔芬结合通过延迟通道从非活性状态进入而影响通道活性，对突变通道的研究证实了结构研究所鉴定的残基的作用。因此，这些研究不仅揭示了开发VGSC靶向治疗药物的潜在新靶点，而且对这种广泛使用的预防药物的脱靶相互作用具有潜在的健康意义。（由英国BBSRC和Rosetrees Trust提供赠款。
In studies aimed at identifying novel compounds which interact with voltage-gated sodium channels (VGSCs), for potential development of new drugs for treating channelopathies, tamoxifen, a drug which is widely used for treatment and prophylactic use in breast cancer was shown to specifically bind with high affinity to the NavMs sodium channel. Our crystallographic studies have demonstrated that the tamoxifen binds into a heretofore unidentified binding site in this channel in a manner that bears resemblance to its binding into its target estrogen receptor. Electrophysiology studies on native and mutated channels (Sula, Hollingworth, Ng, Lamore, DeCaen, Wallace, Molecular Cell, 2021) revealed that tamoxifen binding affects channel activity by delaying channel from the inactive state and studies with mutant channels confirmed the roles of residues identified by the structural studies. These studies thus not only reveal potential new target sites for development of therapeutic drugs targeting in VGSCs, but also have potential health implications for off-target interactions of this widely-used prophylactic drug.(Supported by grants from the UK BBSRC and the Rosetrees Trust.)