Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, 100190, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Nat Commun. 2022 Mar 11;13(1):1286. doi: 10.1038/s41467-022-28808-5.
Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human Na1.3/β1/β2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of Na channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on Na channels and pave a way for subtype-selective therapeutic development.
电压门控钠离子 (Na) 通道在启动和传播动作电位方面发挥着重要作用。Na1.3 参与了许多生理过程，包括神经元发育、激素分泌和疼痛感知。在这里，我们报告了与人 Na1.3/β1/β2 复合物的结构，该复合物与临床使用的药物乌头碱 A 和选择性拮抗剂 ICA121431 结合。乌头碱 A 位于 I 型-II 型窗孔周围，提供了位点 2 神经毒素结合位点的详细视图。它部分阻断离子通道，并扩展了孔衬螺旋，阐明了乌头碱 A 如何降低峰值幅度但提高通道开放概率。相比之下，ICA121431 优先结合激活的 IV 型电压传感器，从而加强了 Ile-Phe-Met 基序与其受体位点的结合，使通道稳定在失活状态，揭示了 Na 通道的变构抑制机制。我们的研究结果提供了不同小分子调节剂结合位点的结构细节，阐明了它们在 Na 通道上的作用的分子机制，并为亚型选择性治疗的发展铺平了道路。
