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Structure paper

TitleStructural basis for Na1.7 inhibition by pore blockers.
Journal, issue, pagesNat Struct Mol Biol, Vol. 29, Issue 12, Page 1208-1216, Year 2022
Publish dateNov 24, 2022
AuthorsJiangtao Zhang / Yiqiang Shi / Zhuo Huang / Yue Li / Bei Yang / Jianke Gong / Daohua Jiang /
PubMed AbstractVoltage-gated sodium channel Na1.7 plays essential roles in pain and odor perception. Na1.7 variants cause pain disorders. Accordingly, Na1.7 has elicited extensive attention in developing new ...Voltage-gated sodium channel Na1.7 plays essential roles in pain and odor perception. Na1.7 variants cause pain disorders. Accordingly, Na1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human Na1.7/β1/β2 complexed with inhibitors XEN907, TC-N1752 and Na1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall. XEN907 directly causes α- to π-helix transition of DIV-S6 helix, which tightens the fast inactivation gate. TC-N1752 induces π-helix transition of DII-S6 helix mediated by a conserved asparagine on DIII-S6, which closes the activation gate. Na1.7-IN2 serves as a pore blocker without causing conformational change. Electrophysiological results demonstrate that XEN907 and TC-N1752 stabilize Na1.7 in inactivated state and delay the recovery from inactivation. Our results provide structural framework for Na1.7 modulation by pore blockers, and important implications for developing subtype-selective analgesics.
External linksNat Struct Mol Biol / PubMed:36424527
MethodsEM (single particle)
Resolution3.07 - 3.22 Å
Structure data

33292

7xm9

EMDB-33292, PDB-7xm9:
Cryo-EM structure of human NaV1.7/beta1/beta2-XEN907
Method: EM (single particle) / Resolution: 3.22 Å

33295

7xmf

EMDB-33295, PDB-7xmf:
Cryo-EM structure of human NaV1.7/beta1/beta2-Nav1.7-IN2
Method: EM (single particle) / Resolution: 3.07 Å

33296

7xmg

EMDB-33296, PDB-7xmg:
Cryo-EM structure of human NaV1.7/beta1/beta2-TCN-1752
Method: EM (single particle) / Resolution: 3.09 Å

Chemicals

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

ChemComp-G2E:
(7~{R})-1'-pentylspiro[6~{H}-furo[3,2-f][1,3]benzodioxole-7,3'-indole]-2'-one

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

ChemComp-G2W:
3-[[4-[3-(4-fluoranyl-2-methyl-phenoxy)azetidin-1-yl]pyrimidin-2-yl]amino]-~{N}-methyl-benzamide

ChemComp-G4I:
(1~{Z})-~{N}-[2-methyl-3-[(~{E})-[6-[4-[[4-(trifluoromethyloxy)phenyl]methoxy]piperidin-1-yl]-1~{H}-1,3,5-triazin-2-ylidene]amino]phenyl]ethanimidic acid

Source
  • homo sapiens (human)
  • aequorea victoria (jellyfish)
KeywordsTRANSPORT PROTEIN / Sodium channel / PROTEIN TRANSPORT

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