Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins.

TitleStructures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins.
Publication TypeJournal Article
Year of Publication2019
AuthorsShen, H, Liu, D, Wu, K, Lei, J, Yan, N
JournalScience
Date Published2019 Feb 14
ISSN1095-9203
Abstract

Voltage-gated sodium channel Nav1.7 represents a promising target for pain relief. Here we report the cryo-EM structures of the human Nav1.7-β1-β2 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 Å. The two structures are nearly identical except for minor shifts of VSDII, 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 VSDIV 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 Nav1.7 and establish the foundation for structure-aided development of analgesics.

DOI10.1126/science.aaw2493
Alternate JournalScience
PubMed ID30765606