@article{a7ee37450bdf4ad788679badf96b2db4,
title = "High-resolution structures of human Nav1.7 reveal gating modulation through α-π helical transition of S6IV",
abstract = "Nav1.7 represents a preeminent target for next-generation analgesics for its critical role in pain sensation. Here we report a 2.2-{\AA} resolution cryo-EM structure of wild-type (WT) Nav1.7 complexed with the β1 and β2 subunits that reveals several previously indiscernible cytosolic segments. Reprocessing of the cryo-EM data for our reported structures of Nav1.7(E406K) bound to various toxins identifies two distinct conformations of S6IV, one composed of α helical turns only and the other containing a π helical turn in the middle. The structure of ligand-free Nav1.7(E406K), determined at 3.5-{\AA} resolution, is identical to the WT channel, confirming that binding of Huwentoxin IV or Protoxin II to VSDII allosterically induces the α → π transition of S6IV. The local secondary structural shift leads to contraction of the intracellular gate, closure of the fenestration on the interface of repeats I and IV, and rearrangement of the binding site for the fast inactivation motif.",
keywords = "CP: Molecular biology, CP: Neuroscience, Huwentoxin IV, Nav1.7, Protoxin II, SCN9A, allosteric modulation, channel gating, cryo-EM structures, fast inactivation, pain, π helix",
author = "Gaoxingyu Huang and Dongliang Liu and Weipeng Wang and Qiurong Wu and Jiaofeng Chen and Xiaojing Pan and Huaizong Shen and Nieng Yan",
note = "Funding Information: We thank Xiaomin Li, Fan Yang, and Jianlin Lei for technical support during EM image acquisition. We thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) for providing the cryo-EM facility support. We thank the Shuimu BioSciences for cryo-EM facility access and technical support during image acquisition. We thank the computational facility support from the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) and Supercomputer Center of Westlake University. This work was funded by the National Natural Science Foundation of China (project 32122032 to H.S.), and the Beijing Nova Program from Beijing Municipal Science and Technology Commission ( Z191100001119127 to X.P.). H.S. acknowledges Westlake University for the startup fund. N.Y., previously supported by multiple grants from the National Natural Science Foundation of China and Ministry of Science and Technology of China for this project, has been supported by the Shirley M. Tilghman endowed professorship after she moved from Tsinghua University to Princeton University in 2017. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = apr,
day = "26",
doi = "10.1016/j.celrep.2022.110735",
language = "English (US)",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}