@article{718d589a7085417aa0c576dcebffb2b9,
title = " Molecular basis for pore blockade of human Na + channel Na v 1.2 by the m-conotoxin KIIIA ",
abstract = " 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, b2, to an overall resolution of 3.0 angstroms. The immunoglobulin domain of b2 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 7 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.",
author = "Xiaojing Pan and Zhangqiang Li and Xiaoshuang Huang and Gaoxingyu Huang and Shuai Gao and Huaizong Shen and Lei Liu and Jianlin Lei and Nieng Yan",
note = "Funding Information: We thank X. Li (Tsinghua University) for technical support during EM image acquisition and C. Zhao and H. Deng at the Protein Chemistry Facility at the Center for Biomedical Analysis of Tsinghua University for mass spectrometric analysis of the protein sample. This work was funded by the National Key Basic Research (973) Program (2015CB910101) and the National Key R&D Program (2016YFA0500402 and 2017YFA0505200) from the Ministry of Science and Technology of China and by the National Natural Science Foundation of China (projects 31800628, 31621092, 31630017, 81861138009, and 91753205). We thank the Tsinghua University Branch of the China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We are grateful for the computational facility support on the cluster of Bio-Computing Platform (Tsinghua University Branch of the China National Center for Protein Sciences, Beijing) and the “Explorer 100” cluster system of Tsinghua National Laboratory for Information Science and Technology. N.Y. is supported by the Shirley M. Tilghman endowed professorship from Princeton University. Publisher Copyright: {\textcopyright} 2017 The Authors.",
year = "2019",
month = mar,
day = "22",
doi = "10.1126/science.aaw2999",
language = "English (US)",
volume = "363",
pages = "1309--1313",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6433",
}