@article{9a743f4d2fe8496a9ea54b0f28ab8c08,
title = " Structures of human Na v 1.7 channel in complex with auxiliary subunits and animal toxins ",
abstract = " Voltage-gated sodium channel Na v 1.7 represents a promising target for pain relief. Here we report the cryo–electron microscopy structures of the human Na v 1.7-b1-b2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with protoxin-II and saxitoxin with huwentoxin-IV, both determined at overall resolutions of 3.2 angstroms. The two structures are nearly identical except for minor shifts of voltage-sensing domain II (VSD II ), whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional protoxin-II sits on top of the S3-S4 linker in VSD IV . The structures may represent an inactivated state with all four VSDs “up” and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Na v 1.7 and establish the foundation for structure-aided development of analgesics.",
author = "Huaizong Shen and Dongliang Liu and Kun Wu and Jianlin Lei and Nieng Yan",
note = "Funding Information: We thank X. Li (Tsinghua University) for technical support during EM image acquisition. 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 the Ministry of Science and Technology of China, and the National Natural Science Foundation of China (projects 31621092, 31630017, and 81861138009 to N.Y.). 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: {\textcopyright} 2017 The Authors.",
year = "2019",
month = mar,
day = "22",
doi = "10.1126/science.aaw2493",
language = "English (US)",
volume = "363",
pages = "1303--1308",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6433",
}