ジャーナル: Science / 年: 2019 タイトル: Molecular basis for pore blockade of human Na channel Na1.2 by the μ-conotoxin KIIIA. 著者: Xiaojing Pan / Zhangqiang Li / Xiaoshuang Huang / Gaoxingyu Huang / Shuai Gao / Huaizong Shen / Lei Liu / Jianlin Lei / Nieng Yan / 要旨: The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human ...The voltage-gated sodium channel Na1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo-electron microscopy structure of human Na1.2 bound to a peptidic pore blocker, the μ-conotoxin KIIIA, in the presence of an auxiliary subunit, β2, to an overall resolution of 3.0 angstroms. The immunoglobulin domain of β2 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 Lys at the entrance to the selectivity filter. Many interacting residues are specific to Na1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for the rational design of subtype-specific blockers for Na channels.
根拠: microscopy, SDS-PAGE and Mass-spectrometry idenitified the presence of Nav1.2 alpha subunit and the beta2 subunit. The presence of KIIIA was confirmed by electron density analysis.
タイプ
名称
対称操作
数
identity operation
1_555
1
Buried area
4760 Å2
ΔGint
1 kcal/mol
Surface area
67280 Å2
-
要素
-
Sodium channel ... , 2種, 2分子 CA
#1: タンパク質
Sodiumchannelsubunitbeta-2 / ナトリウムチャネル
分子量: 14267.261 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: SCN2B, UNQ326/PRO386 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: O60939
#2: タンパク質
Sodiumchannelproteintype2subunitalpha / ナトリウムチャネル / HBSC II / Sodium channel protein brain II subunit alpha / Sodium channel protein type II subunit ...HBSC II / Sodium channel protein brain II subunit alpha / Sodium channel protein type II subunit alpha / Voltage-gated sodium channel subunit alpha Nav1.2
分子量: 232800.172 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: SCN2A, NAC2, SCN2A1, SCN2A2 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: Q99250