TY - JOUR
T1 - Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1
AU - Pan, Xiaojing
AU - Li, Zhangqiang
AU - Zhou, Qiang
AU - Shen, Huaizong
AU - Wu, Kun
AU - Huang, Xiaoshuang
AU - Chen, Jiaofeng
AU - Zhang, Juanrong
AU - Zhu, Xuechen
AU - Lei, Jianlin
AU - Xiong, Wei
AU - Gong, Haipeng
AU - Xiao, Bailong
AU - Yan, Nieng
N1 - Funding Information:
This work was funded by the National Key Basic Research (973) Program (2015CB910101 to N.Y.) and the National Key R&D Program (2016YFA0500402 to N.Y. and 2016YFA0501100 to J.L.) from Ministry of Science and Technology of China, the National Natural Science Foundation of China (projects 31621092, 31630017, and 81861138009 to N.Y.), and China Postdoctoral Science Foundation (BX201600089 to X.P.). We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We thank the computational facility support on the cluster of Bio-Computing Platform (Tsinghua University Branch of 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:
© 2017 The Author(s).
PY - 2018/10/19
Y1 - 2018/10/19
N2 - Voltage-gated sodium (Nav) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Nav channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Nav1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the b1 subunit, providing insight into the molecular basis for Na+ permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Nav channels. The structure provides a path toward mechanistic investigation of Nav channels and drug discovery for Nav channelopathies.
AB - Voltage-gated sodium (Nav) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Nav channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Nav1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the b1 subunit, providing insight into the molecular basis for Na+ permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Nav channels. The structure provides a path toward mechanistic investigation of Nav channels and drug discovery for Nav channelopathies.
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U2 - 10.1126/science.aau2486
DO - 10.1126/science.aau2486
M3 - Article
C2 - 30190309
AN - SCOPUS:85055206651
SN - 0036-8075
VL - 362
JO - Science
JF - Science
IS - 6412
M1 - eaau2486
ER -