Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1E 7HX, UK.
Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Mol Cell. 2021 Mar 18;81(6):1160-1169.e5. doi: 10.1016/j.molcel.2020.12.048. Epub 2021 Jan 26.
Voltage-gated sodium channels are targets for many analgesic and antiepileptic drugs whose therapeutic mechanisms and binding sites have been well characterized. We describe the identification of a previously unidentified receptor site within the NavMs voltage-gated sodium channel. Tamoxifen, an estrogen receptor modulator, and its primary and secondary metabolic products bind at the intracellular exit of the channel, which is a site that is distinct from other previously characterized sodium channel drug sites. These compounds inhibit NavMs and human sodium channels with similar potencies and prevent sodium conductance by delaying channel recovery from the inactivated state. This study therefore not only describes the structure and pharmacology of a site that could be leveraged for the development of new drugs for the treatment of sodium channelopathies but may also have important implications for off-target health effects of this widely used therapeutic drug.
电压门控钠离子通道是许多镇痛药和抗癫痫药的作用靶点，其治疗机制和结合部位已得到很好的描述。我们描述了在 NavMs 电压门控钠离子通道内发现一个以前未被识别的受体部位。他莫昔芬是一种雌激素受体调节剂，及其主要和次要代谢产物结合在通道的细胞内出口处，该部位与其他先前描述的钠离子通道药物结合部位不同。这些化合物以相似的效价抑制 NavMs 和人源钠离子通道，并通过延迟通道从失活状态恢复来阻止钠离子电导。因此，这项研究不仅描述了一个可能被用于开发治疗钠离子通道病新药的靶点的结构和药理学，而且可能对这种广泛使用的治疗药物的脱靶健康影响具有重要意义。
