Title : Structures of human
Nav1.7 channel in complex with auxiliary subunits and animal toxins
Abstract :
- Voltage-gated sodium channel Nav1.7 represents a promising target for pain relief
- Here we report the cryo-electron microscopy structures of the human Nav1.7-β1-β 2 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 (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