Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins
Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins
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DOI：
10.1126/science.aaw2493
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发表时间：
2019-03-22
期刊：
影响因子：
56.9
通讯作者：
Yan, Nieng
中科院分区：
文献类型：
--
作者：
Shen, Huaizong;Liu, Dongliang;Yan, Nieng
电压门控钠通道Na(v)1.7是缓解疼痛的一个有希望的靶点。在这里，我们报道了人类Na(v)1.7- β 1- β 2复合物与两种孔阻滞剂和门控修饰毒素（GMTs）结合的低温电子显微镜结构，河蚌毒素与原毒素- ii结合，蛤蚌毒素与虎文毒素- iv结合，两者的总分辨率均为3.2埃。这两种结构几乎相同，除了电压感应域II （VSDII）的微小位移，其S3-S4连接器以类似的方式容纳两个gmt。另外一个原毒素ii位于VSDIV中S3-S4连接体的顶部。这些结构可能表现为失活状态，所有四个vsd都“上”，细胞内门关闭。这些结构阐明了Na(v)1.7的功能和疾病的机制理解，并为结构辅助镇痛药的开发奠定了基础。
Voltage-gated sodium channel Na(v)1.7 represents a promising target for pain relief. Here we report the cryo-electron microscopy structures of the human Na(v)1.7-beta 1-beta 2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with protoxin-II and saxitoxin with huwentoxin-IV, both determined at overall resolutions of 3.2 angstroms. The two structures are nearly identical except for minor shifts of voltage-sensing domain II (VSDII), whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional protoxin-II sits on top of the S3-S4 linker in VSDIV. The structures may represent an inactivated state with all four VSDs "up" and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Na(v)1.7 and establish the foundation for structure-aided development of analgesics.