Molecular basis for pore blockade of human Na+ channel Nav1.2 by the μ-conotoxin KIIIA

被引：202

作者：

Pan, Xiaojing ^{[1
,2
,3
,4
]}

Li, Zhangqiang ^{[1
,2
,3
,4
]}

Huang, Xiaoshuang ^{[1
,2
,3
,4
]}

Huang, Gaoxingyu ^{[1
,2
,3
,4
]}

Gao, Shuai ^{[5
,7
]}

Shen, Huaizong ^{[1
,2
,3
,4
]}

Liu, Lei ^{[2
,3
,5
]}

Lei, Jianlin ^{[6
]}

Yan, Nieng ^{[1
,2
,3
,4
,7
]}

机构：

[1] Tsinghua Univ, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China

[2] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China

[3] Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Sch Life Sci, Beijing 100084, Peoples R China

[4] Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Sch Life Sci, Beijing 100084, Peoples R China

[5] Tsinghua Univ, Dept Chem, Beijing 100084, Peoples R China

[6] Tsinghua Univ, Sch Life Sci, Technol Ctr Prot Sci, Minist Educ,Key Lab Prot Sci, Beijing 100084, Peoples R China

[7] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

来源：

SCIENCE | 2019年 / 363卷 / 6433期

基金：

中国国家自然科学基金;

关键词：

SODIUM-CHANNEL; SAXITOXIN RECEPTOR; AUXILIARY SUBUNIT; RAT-BRAIN; MUTATIONS; TETRODOTOXIN; EXPRESSION; SPECTRUM; FEBRILE; BETA-3;

D O I：

10.1126/science.aaw2999

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：

The voltage-gated sodium channel Na(v)1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human Na(v)1.2 bound to a peptidic pore blocker, the m-conotoxin KIIIA, in the presence of an auxiliary subunit, beta 2, to an overall resolution of 3.0 angstroms. The immunoglobulin domain of beta 2 interacts with the shoulder of the pore domain through a disulfide bond. The 16-residue KIIIA interacts with the extracellular segments in repeats I to III, placing Lys7 at the entrance to the selectivity filter. Many interacting residues are specific to Na(v)1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for the rational design of subtype-specific blockers for Na-v channels.

引用

页码：1309 / +

页数：27

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