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Stabilization of the GluCl Ligand-Gated Ion Channel in the Presence and Absence of Ivermectin
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.ORCID iD: 0000-0001-8354-0253
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, SeRC - Swedish e-Science Research Centre.
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2013 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 105, no 3, 640-647 p.Article in journal (Refereed) Published
Abstract [en]

Improving our understanding of the mechanisms and effects of anesthetics is a critically important part of neuroscience. The currently dominant theory is that anesthetics and similar molecules act by binding to Cys-loop receptors in the postsynaptic terminal of nerve cells and potentiate or inhibit their function. Although structures for some of the most important mammalian channels have still not been determined, a number of important results have been derived from work on homologous cationic channels in bacteria. However, partly due to the lack of a nervous system in bacteria, there are a number of questions about how these results relate to higher organisms. The recent determination of a structure of the eukaryotic chloride channel, GluCl, is an important step toward accurate modeling of mammalian channels, because it is more similar in function to human Cys-loop receptors such as GABA(A)R or GlyR. One potential issue with using GluCl to model other receptors is the presence of the large ligand ivermectin (IVM) positioned between all five subunits. Here, we have performed a series of microsecond molecular simulations to study how the dynamics and structure of GluCl change in the presence versus absence of IVM. When the ligand is removed, subunits move at least 2 angstrom closer to each other compared to simulations with IVM bound. In addition, the pore radius shrinks to 1.2 angstrom, all of which appears to support a model where IVM binding between subunits stabilizes an open state, and that the relaxed nonIVM conformations might be suitable for modeling other channels. Interestingly, the presence of IVM also has an effect on the structure of the important loop C located at the neurotransmitter-binding pocket, which might help shed light on its partial agonist behavior.

Place, publisher, year, edition, pages
2013. Vol. 105, no 3, 640-647 p.
Keyword [en]
Receptor Chloride Channel, X-Ray-Structure, Molecular-Dynamics, Glycine Receptor, Gaba(A) Receptor, Binding, Conformation, Simulations, Permeation, Activation
National Category
URN: urn:nbn:se:kth:diva-127748DOI: 10.1016/j.bpj.2013.06.037ISI: 000323141100014ScopusID: 2-s2.0-84881394637OAI: diva2:646407
EU, European Research Council, 209825Swedish Research Council, 2010-491 2010-5107Swedish Foundation for Strategic Research Swedish e‐Science Research CenterScience for Life Laboratory - a national resource center for high-throughput molecular bioscience

QC 20140623

Available from: 2013-09-09 Created: 2013-09-05 Last updated: 2016-05-18Bibliographically 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.
TRITA-FYS, ISSN 0280-316X ; 2016:26
ion channel, gating, simulation, molecular dynamics, receptor, cys-loop, modelling
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Research subject
Theoretical Chemistry and Biology; Biological Physics
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)

QC 20160518

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

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Yoluk, ÖzgeBrömstrup, TorbenLindahl, Erik
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