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Science. 2019 Feb 14. pii: eaaw2493. doi: 10.1126/science.aaw2493. [Epub ahead of print]

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

Shen H1,2,3, Liu D1,2,3, Wu K4, Lei J2,5, Yan N6,2,3.

Author information

1
State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China.
2
Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China.
3
Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
4
Medical Research Center, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
5
Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
6
State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China. nyan@princeton.edu.

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.

PMID:
30765606
DOI:
10.1126/science.aaw2493

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