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TitleStructures of human Na1.7 channel in complex with auxiliary subunits and animal toxins.
Journal, issue, pagesScience, Vol. 363, Issue 6433, Page 1303-1308, Year 2019
Publish dateMar 22, 2019
AuthorsHuaizong Shen / Dongliang Liu / Kun Wu / Jianlin Lei / Nieng Yan /
PubMed AbstractVoltage-gated sodium channel Na1.7 represents a promising target for pain relief. Here we report the cryo-electron microscopy structures of the human Na1.7-β1-β2 complex bound to two combinations ...Voltage-gated sodium channel Na1.7 represents a promising target for pain relief. Here we report the cryo-electron microscopy structures of the human Na1.7-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 angstroms. The two structures are nearly identical except for minor shifts of voltage-sensing domain II (VSD), 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 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 Na1.7 and establish the foundation for structure-aided development of analgesics.
External linksScience / PubMed:30765606
MethodsEM (single particle)
Resolution3.2 Å
Structure data

9781

6j8g

6j8h

EMDB-9781: Structure of human voltage-gated sodium channel Nav1.7 in complex with auxiliary beta subunits, huwentoxin-IV and saxitoxin
PDB-6j8g: Structure of human voltage-gated sodium channel Nav1.7 in complex with auxiliary beta subunits, huwentoxin-IV and saxitoxin (Y1755 up)
PDB-6j8h: Structure of human voltage-gated sodium channel Nav1.7 in complex with auxiliary beta subunits, huwentoxin-IV and saxitoxin (Y1755 down)
Method: EM (single particle) / Resolution: 3.2 Å

9782

6j8i

6j8j

EMDB-9782: Structure of human voltage-gated sodium channel Nav1.7 in complex with auxiliary beta subunits, ProTx-II and tetrodotoxin
PDB-6j8i: Structure of human voltage-gated sodium channel Nav1.7 in complex with auxiliary beta subunits, ProTx-II and tetrodotoxin (Y1755 up)
PDB-6j8j: Structure of human voltage-gated sodium channel Nav1.7 in complex with auxiliary beta subunits, ProTx-II and tetrodotoxin (Y1755 down)
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-9SL:
[(3aS,4R,10aS)-2,6-diamino-10,10-dihydroxy-3a,4,9,10-tetrahydro-3H,8H-pyrrolo[1,2-c]purin-4-yl]methyl carbamate / neurotoxin*YM / Saxitoxin

ChemComp-9SR:
(1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.1~7,11~.0~1,6~]tetradec-3-ene-5,9,12,13,14-pentol (non-preferred name) / neurotoxin*YM / Tetrodotoxin

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / voltage-gated sodium channel

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