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-Structure paper
タイトル | Structure of human Na1.6 channel reveals Na selectivity and pore blockade by 4,9-anhydro-tetrodotoxin. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 1030, Year 2023 |
掲載日 | 2023年2月23日 |
著者 | Yue Li / Tian Yuan / Bo Huang / Feng Zhou / Chao Peng / Xiaojing Li / Yunlong Qiu / Bei Yang / Yan Zhao / Zhuo Huang / Daohua Jiang / |
PubMed 要旨 | The sodium channel Na1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na1.6 has been ...The sodium channel Na1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human Na1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of Na1.6 inhibition by the blocker. The apo-form structure reveals two potential Na binding sites within the selectivity filter, suggesting a possible mechanism for Na selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into Na1.6 structure, ion conductance, and inhibition. |
リンク | Nat Commun / PubMed:36823201 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.3 - 3.4 Å |
構造データ | EMDB-34387, PDB-8gz1: EMDB-34388, PDB-8gz2: |
化合物 | ChemComp-NAG: ChemComp-NA: ChemComp-WMK: |
由来 |
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キーワード | MEMBRANE PROTEIN / ion channal |