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Conformational Gating Dynamics in the GluCl Anion-Selective Chloride Channel
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.ORCID iD: 0000-0001-8354-0253
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. Stockholm Univ, Dept Biochem & Biophys, Ctr Biomembrane Res.ORCID iD: 0000-0002-2734-2794
KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.ORCID iD: 0000-0002-3364-6647
2015 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 6, no 8, 1459-1467 p.Article 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, 1459-1467 p.
Keyword [en]
Membrane protein, ligand-gated ion channel, cys-loop receptor, molecular dynamics simulations
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-173445DOI: 10.1021/acschemneuro.5b00111ISI: 000359967300022PubMedID: 25992588Scopus ID: 2-s2.0-84939864190OAI: oai:DiVA.org:kth-173445DiVA: diva2:855040
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20171128

Available from: 2015-09-18 Created: 2015-09-11 Last updated: 2017-11-28Bibliographically approved
In thesis
1. Elucidating the Gating Mechanism of Cys-Loop Receptors
Open this publication in new window or tab >>Elucidating the Gating Mechanism of Cys-Loop Receptors
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cys-loop receptors are membrane proteins that are key players for the fast synaptic neurotransmission. Their ion transport initiates new nerve signals after activation by small agonist molecules, but this function is also highly sensitive to allosteric modulation by a number of compounds such as anesthetics, alcohol or anti-parasitic agents. For a long time, these modulators were believed to act primarily on the membrane, but the availability of high- resolution structures has made it possible to identify several binding sites in the transmembrane domains of the ion channels. It is known that ligand binding in the extracellular domain causes a conformational earthquake that interacts with the transmembrane domain, which leads to channel opening. The investigations carried out in this thesis aim at understanding the connection between ligand binding and channel opening.

I present new models of the mammalian GABAA receptor based on the eukaryotic structure GluCl co-crystallized with an anti-parasitic agent, and show how these models can be used to study receptor-modulator interactions. I also show how removal of the bound modulator leads to gradual closing of the channel in molecular dynamics simulations. In contrast, simulations of the receptor with both the agonist and the modulator remain stable in an open-like conformation. This makes it possible to extract several key interactions, and I propose mechanisms for how the extracellular domain motion is initiated. The rapid increase in the number of cys-loop receptor structures the last few years has further made it possible to use principal component analysis (PCA) to create low-dimensional descriptions of the conformational landscape. By performing PCA on the crystal structure ensemble, I have been able to divide the structures into functional clusters and sample the transitions between them using various sampling methods.

The studies presented in this thesis contribute to our understanding of the gating mechanism and the functional clustering of the cys-loop receptor structures, which both are important to design new allosteric modulator drugs that influence the channel function, in particular to treat neurological disorders.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2016. 72 p.
Series
TRITA-FYS, ISSN 0280-316X ; 2016:26
Keyword
ion channel, gating, simulation, molecular dynamics, receptor, cys-loop, modelling
National Category
Biophysics
Research subject
Theoretical Chemistry and Biology; Biological Physics
Identifiers
urn:nbn:se:kth:diva-187230 (URN)978-91-7729-009-4 (ISBN)
Public defence
2016-06-13, sal F3, Lindstedtsvägen 26, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

QC 20160518

Available from: 2016-05-18 Created: 2016-05-18 Last updated: 2016-05-20Bibliographically approved

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Yoluk, OzgeLindahl, Erik

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