Voltage-dependent structural models of the human Hv1 proton channel from long-timescale molecular dynamics simulations.

Szczegóły
Abstrakt

Tytuł:: Voltage-dependent structural models of the human Hv1 proton channel from long-timescale molecular dynamics simulations.
Autorzy:: Geragotelis AD; Department of Chemistry, University of California, Irvine, CA 92697.
Wood ML; Department of Chemistry, University of California, Irvine, CA 92697.
Göddeke H; Theoretical Chemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, D-44780 Bochum, Germany.
Hong L; Department of Physiology and Biophysics, University of California, Irvine, CA 92697.
Webster PD; Department of Physiology and Biophysics, University of California, Irvine, CA 92697.; Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697.
Wong EK; Department of Chemistry, University of California, Irvine, CA 92697.
Freites JA; Department of Chemistry, University of California, Irvine, CA 92697.
Tombola F; Department of Physiology and Biophysics, University of California, Irvine, CA 92697.; Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697.
Tobias DJ; Department of Chemistry, University of California, Irvine, CA 92697; .
Źródło:: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jun 16; Vol. 117 (24), pp. 13490-13498. Date of Electronic Publication: 2020 May 27.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
Język:: English
Imprint Name(s):: Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms:: Ion Channel Gating*
Ion Channels/*chemistry
Ion Channels/*metabolism
Crystallography, X-Ray ; Guanidines/metabolism ; Humans ; Hydrogen Bonding ; Ion Channels/genetics ; Membrane Potentials ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Mutation ; Protein Conformation ; Protons
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Grant Information:: R01 GM098973 United States GM NIGMS NIH HHS; R01 GM116961 United States GM NIGMS NIH HHS
Contributed Indexing:: Keywords: Hv1 proton channel; closed state model; ion channels; molecular dynamics simulations; open state model
Substance Nomenclature:: 0 (Guanidines)
0 (HVCN1 protein, human)
0 (Ion Channels)
0 (Protons)
5418-95-1 (2-benzimidazolylguanidine)
Entry Date(s):: Date Created: 20200529 Date Completed: 20200908 Latest Revision: 20211101
Update Code:: 20240105
PubMed Central ID:: PMC7306757
DOI:: 10.1073/pnas.1920943117
PMID:: 32461356
: Czasopismo naukowe

The voltage-gated Hv1 proton channel is a ubiquitous membrane protein that has roles in a variety of cellular processes, including proton extrusion, pH regulation, production of reactive oxygen species, proliferation of cancer cells, and increased brain damage during ischemic stroke. A crystal structure of an Hv1 construct in a putative closed state has been reported, and structural models for the channel open state have been proposed, but a complete characterization of the Hv1 conformational dynamics under an applied membrane potential has been elusive. We report structural models of the Hv1 voltage-sensing domain (VSD), both in a hyperpolarized state and a depolarized state resulting from voltage-dependent conformational changes during a 10-μs-timescale atomistic molecular dynamics simulation in an explicit membrane environment. In response to a depolarizing membrane potential, the S4 helix undergoes an outward displacement, leading to changes in the VSD internal salt-bridge network, resulting in a reshaping of the permeation pathway and a significant increase in hydrogen bond connectivity throughout the channel. The total gating charge displacement associated with this transition is consistent with experimental estimates. Molecular docking calculations confirm the proposed mechanism for the inhibitory action of 2-guanidinobenzimidazole (2GBI) derived from electrophysiological measurements and mutagenesis. The depolarized structural model is also consistent with the formation of a metal bridge between residues located in the core of the VSD. Taken together, our results suggest that these structural models are representative of the closed and open states of the Hv1 channel.
Competing Interests: The authors declare no competing interest.

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