Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins

被引：323
作者：
Shen, Huaizong [1 ,2 ,3 ,4 ]
Liu, Dongliang [1 ,2 ,3 ,4 ]
Wu, Kun [5 ]
Lei, Jianlin [2 ,6 ]
Yan, Nieng [1 ,2 ,3 ,4 ]
机构：
[1] Tsinghua Univ, State Key Lab Membrane Biol, Beijing 100084, Peoples R China
[2] Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Beijing 100084, Peoples R China
[3] Tsinghua Univ, Sch Life Sci, Tsinghua Peking Joint Ctr Life Sci, Beijing 100084, Peoples R China
[4] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China
[5] Capital Med Univ, Beijing Chao Yang Hosp, Med Res Ctr, Beijing Key Lab Cardiopulm Cerebral Resuscitat, Beijing 100020, Peoples R China
[6] Tsinghua Univ, Sch Life Sci, Technol Ctr Prot Sci, Minist Educ,Key Lab Prot Sci, Beijing 100084, Peoples R China
来源：
SCIENCE | 2019年 / 363卷 / 6433期
基金：
中国国家自然科学基金;
关键词：
II VOLTAGE SENSOR; LONG QT SYNDROME; SODIUM-CHANNELS; HUWENTOXIN-IV; PROTX-II; LIPID-MEMBRANES; PAIN; TETRODOTOXIN; MUTATIONS; INHIBITION;
D O I：
10.1126/science.aaw2493
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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.
引用
收藏
页码：1303 / +
页数：34
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