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TitleDissection of the structure-function relationship of Na channels.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 121, Issue 9, Page e2322899121, Year 2024
Publish dateFeb 27, 2024
AuthorsZhangqiang Li / Qiurong Wu / Gaoxingyu Huang / Xueqin Jin / Jiaao Li / Xiaojing Pan / Nieng Yan /
PubMed AbstractVoltage-gated sodium channels (Na) undergo conformational shifts in response to membrane potential changes, a mechanism known as the electromechanical coupling. To delineate the structure-function ...Voltage-gated sodium channels (Na) undergo conformational shifts in response to membrane potential changes, a mechanism known as the electromechanical coupling. To delineate the structure-function relationship of human Na channels, we have performed systematic structural analysis using human Na1.7 as a prototype. Guided by the structural differences between wild-type (WT) Na1.7 and an eleven mutation-containing variant, designated Na1.7-M11, we generated three additional intermediate mutants and solved their structures at overall resolutions of 2.9-3.4 Å. The mutant with nine-point mutations in the pore domain (PD), named Na1.7-M9, has a reduced cavity volume and a sealed gate, with all voltage-sensing domains (VSDs) remaining up. Structural comparison of WT and Na1.7-M9 pinpoints two residues that may be critical to the tightening of the PD. However, the variant containing these two mutations, Na1.7-M2, or even in combination with two additional mutations in the VSDs, named Na1.7-M4, failed to tighten the PD. Our structural analysis reveals a tendency of PD contraction correlated with the right shift of the static inactivation I-V curves. We predict that the channel in the resting state should have a "tight" PD with down VSDs.
External linksProc Natl Acad Sci U S A / PubMed:38381792 / PubMed Central
MethodsEM (single particle)
Resolution2.89 - 3.39 Å
Structure data

EMDB-38482, PDB-8xmm:
Voltage-gated sodium channel Nav1.7 variant M9
Method: EM (single particle) / Resolution: 2.89 Å

EMDB-38483, PDB-8xmn:
Voltage-gated sodium channel Nav1.7 variant M2
Method: EM (single particle) / Resolution: 3.37 Å

EMDB-38484, PDB-8xmo:
Voltage-gated sodium channel Nav1.7 variant M4
Method: EM (single particle) / Resolution: 3.39 Å

Chemicals

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

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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

ChemComp-1PW:
(2S,3R,4E)-2-(acetylamino)-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate

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

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

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