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Conformational Gating Dynamics in the GluCl Anion-Selective Chloride Channel
KTH, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-8354-0253
KTH, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-2734-2794
Science for Life Laboratory; Theoretical and Computational Biophysics, Department of Theoretical Physics, KTH Royal Institute of Technology, Stockholm, Sweden.ORCID iD: 0000-0002-3364-6647
2015 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 6, no 8, p. 1459-1467Article in journal (Refereed) Published
Abstract [en]

Cys-loop receptors are central to propagation of signals in the nervous system. The gating of the membrane-spanning pore is triggered by structural rearrangements in the agonist-binding site, located some so A away from the pore. A sequential conformational change, propagating from the ligand-binding site to the pore, has been proposed to govern gating in all Cys-loop receptors. Here, we identify structural and dynamic components of the conformational gating in the eukaryotic glutamate-gated chloride channel (GluCl) by means of molecular dynamics (MD) simulations with and without the L-glutamate agonist bound. A significant increase in pore opening and accompanying hydration is observed in the presence of glutamate. Potential of mean force calculations reveal that the barrier for ion passage drops from 15 kcal/mol to 5-10 kcal/mol with the agonist bound. This appears to be explained by agonist binding that leads to significant changes in the intersubunit hydrogen-bonding pattern, which induce a slight tilt of the extracellular domain relative to the transmembrane domain in the simulations. This rearrangement is subtle, but correspond to the direction of the quaternary twist observed as a key difference between open and closed X-ray structures. While the full reversible gating is still a much slower process, the observed structural dynamics sheds new light on the early stages of how the agonist influences the extracellular domain, how the extracellular domain interacts with the transmembrane domain, and how changes in the transmembrane domain alter the free energy of ion passage.

Place, publisher, year, edition, pages
American Chemical Society (ACS) , 2015. Vol. 6, no 8, p. 1459-1467
Keywords [en]
Membrane protein, ligand-gated ion channel, cys-loop receptor, molecular dynamics simulations
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-153207DOI: 10.1021/acschemneuro.5b00111ISI: 000359967300022PubMedID: 25992588Scopus ID: 2-s2.0-84939864190OAI: oai:DiVA.org:umu-153207DiVA, id: diva2:1261897
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20171128

Available from: 2018-11-08 Created: 2018-11-08 Last updated: 2018-11-09Bibliographically approved

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Andersson, Magnus

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