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-Structure paper
Title | Dissection of the structure-function relationship of Na channels. |
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Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 121, Issue 9, Page e2322899121, Year 2024 |
Publish date | Feb 27, 2024 |
![]() | Zhangqiang Li / Qiurong Wu / Gaoxingyu Huang / Xueqin Jin / Jiaao Li / Xiaojing Pan / Nieng Yan / ![]() |
PubMed Abstract | 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 ...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. |
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Methods | EM (single particle) |
Resolution | 2.89 - 3.39 Å |
Structure data | EMDB-38482, PDB-8xmm: EMDB-38483, PDB-8xmn: EMDB-38484, PDB-8xmo: |
Chemicals | ![]() ChemComp-NAG: ![]() ChemComp-CLR: ![]() ChemComp-LPE: ![]() ChemComp-1PW: ![]() ChemComp-PCW: ![]() ChemComp-P5S: |
Source |
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![]() | MEMBRANE PROTEIN / Voltage-gated sodium channel |