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-Structure paper
Title | Structural basis for modulation of human Na1.3 by clinical drug and selective antagonist. |
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Journal, issue, pages | Nat Commun, Vol. 13, Issue 1, Page 1286, Year 2022 |
Publish date | Mar 11, 2022 |
Authors | Xiaojing Li / Feng Xu / Hao Xu / Shuli Zhang / Yiwei Gao / Hongwei Zhang / Yanli Dong / Yanchun Zheng / Bei Yang / Jianyuan Sun / Xuejun Cai Zhang / Yan Zhao / Daohua Jiang / |
PubMed Abstract | Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, ...Voltage-gated sodium (Na) channels play fundamental roles in initiating and propagating action potentials. Na1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human Na1.3/β1/β2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of Na channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on Na channels and pave a way for subtype-selective therapeutic development. |
External links | Nat Commun / PubMed:35277491 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.3 - 3.35 Å |
Structure data | EMDB-32341, PDB-7w77: EMDB-32343, PDB-7w7f: |
Chemicals | ChemComp-NAG: ChemComp-9Z9: ChemComp-6OU: ChemComp-966: ChemComp-8DE: |
Source |
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Keywords | MEMBRANE PROTEIN / Ion channel / Drug / Antagonist |