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Structure paper

TitleStructural basis for high-voltage activation and subtype-specific inhibition of human Na1.8.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 119, Issue 30, Page e2208211119, Year 2022
Publish dateJul 26, 2022
AuthorsXiaoshuang Huang / Xueqin Jin / Gaoxingyu Huang / Jian Huang / Tong Wu / Zhangqiang Li / Jiaofeng Chen / Fang Kong / Xiaojing Pan / Nieng Yan /
PubMed AbstractThe dorsal root ganglia-localized voltage-gated sodium (Na) channel Na1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Na1.8 is the ...The dorsal root ganglia-localized voltage-gated sodium (Na) channel Na1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Na1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Na1.8 alone and bound to a selective pore blocker, A-803467, at overall resolutions of 2.7 to 3.2 Å. The first voltage-sensing domain (VSD) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSD and the pore domain (PD) to be a determinant for the high-voltage dependence of activation. A-803467 was clearly resolved in the central cavity of the PD, clenching S6. Our structure-guided functional characterizations show that two nonligand binding residues, Thr397 on S6 and Gly1406 on S6, allosterically modulate the channel's sensitivity to A-803467. Comparison of available structures of human Na channels suggests the extracellular loop region to be a potential site for developing subtype-specific pore-blocking biologics.
External linksProc Natl Acad Sci U S A / PubMed:35858452 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.2 Å
Structure data

32439

7we4

EMDB-32439, PDB-7we4:
Human Nav1.8 with A-803467, class I
Method: EM (single particle) / Resolution: 2.7 Å

32451

7wel

EMDB-32451, PDB-7wel:
Human Nav1.8 with A-803467, class II
Method: EM (single particle) / Resolution: 3.2 Å

32475

7wfr

EMDB-32475, PDB-7wfr:
Human Nav1.8 with A-803467, class III
Method: EM (single particle) / Resolution: 3.0 Å

32476

7wfw

EMDB-32476, PDB-7wfw:
Apo human Nav1.8
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

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

ChemComp-95T:
5-(4-chlorophenyl)-~{N}-(3,5-dimethoxyphenyl)furan-2-carboxamide

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

ChemComp-LPE:
1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

ChemComp-P5S:
O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine / Phosphatidylserine

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

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