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An open state of a voltage-gated sodium channel involving a π-helix and conserved pore-facing asparagine
Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-6855-9295
Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0003-2049-3378
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Number of Authors: 52022 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 121, no 1, p. 11-22Article in journal (Refereed) Published
Abstract [en]

Voltage-gated sodium (Nav) channels play critical roles in propagating action potentials and otherwise manipulating ionic gradients in excitable cells. These channels open in response to membrane depolarization, selectively permeating sodium ions until rapidly inactivating. Structural characterization of the gating cycle in this channel family has proved challenging, particularly due to the transient nature of the open state. A structure from the bacterium Magnetococcus marinus Nav (NavMs) was initially proposed to be open, based on its pore diameter and voltage-sensor conformation. However, the functional annotation of this model, and the structural details of the open state, remain disputed. In this work, we used molecular modeling and simulations to test possible open-state models of NavMs. The full-length experimental structure, termed here the α-model, was consistently dehydrated at the activation gate, indicating an inability to conduct ions. Based on a spontaneous transition observed in extended simulations, and sequence/structure comparison to other Nav channels, we built an alternative π-model featuring a helix transition and the rotation of a conserved asparagine residue into the activation gate. Pore hydration, ion permeation, and state-dependent drug binding in this model were consistent with an open functional state. This work thus offers both a functional annotation of the full-length NavMs structure and a detailed model for a stable Nav open state, with potential conservation in diverse ion-channel families.

Place, publisher, year, edition, pages
2022. Vol. 121, no 1, p. 11-22
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Biological Sciences
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URN: urn:nbn:se:su:diva-201088DOI: 10.1016/j.bpj.2021.12.010ISI: 000740815400004PubMedID: 34890580Scopus ID: 2-s2.0-85121494441OAI: oai:DiVA.org:su-201088DiVA, id: diva2:1633233
Available from: 2022-01-28 Created: 2022-01-28 Last updated: 2022-05-30Bibliographically approved

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McComas, SarahHoward, Rebecca J.

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