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Stabilization of the GluCl Ligand-Gated Ion Channel in the Presence and Absence of Ivermectin
KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Centra, SeRC - Swedish e-Science Research Centre.ORCID-id: 0000-0001-8354-0253
KTH, Skolan för teknikvetenskap (SCI), Teoretisk fysik, Beräkningsbiofysik. KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Centra, SeRC - Swedish e-Science Research Centre.
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2013 (Engelska)Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 105, nr 3, s. 640-647Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2013. Vol. 105, nr 3, s. 640-647
Nyckelord [en]
Receptor Chloride Channel, X-Ray-Structure, Molecular-Dynamics, Glycine Receptor, Gaba(A) Receptor, Binding, Conformation, Simulations, Permeation, Activation
Nationell ämneskategori
Biofysik
Identifikatorer
URN: urn:nbn:se:kth:diva-127748DOI: 10.1016/j.bpj.2013.06.037ISI: 000323141100014Scopus ID: 2-s2.0-84881394637OAI: oai:DiVA.org:kth-127748DiVA, id: diva2:646407
Forskningsfinansiär
EU, Europeiska forskningsrådet, 209825Vetenskapsrådet, 2010-491 2010-5107Stiftelsen för strategisk forskning (SSF)Swedish e‐Science Research CenterScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Anmärkning

QC 20140623

Tillgänglig från: 2013-09-09 Skapad: 2013-09-05 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Ingår i avhandling
1. Elucidating the Gating Mechanism of Cys-Loop Receptors
Öppna denna publikation i ny flik eller fönster >>Elucidating the Gating Mechanism of Cys-Loop Receptors
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: KTH Royal Institute of Technology, 2016. s. 72
Serie
TRITA-FYS, ISSN 0280-316X ; 2016:26
Nyckelord
ion channel, gating, simulation, molecular dynamics, receptor, cys-loop, modelling
Nationell ämneskategori
Biofysik
Forskningsämne
Teoretisk kemi och biologi; Biologisk fysik
Identifikatorer
urn:nbn:se:kth:diva-187230 (URN)978-91-7729-009-4 (ISBN)
Disputation
2016-06-13, sal F3, Lindstedtsvägen 26, Stockholm, 14:00 (Engelska)
Opponent
Handledare
Anmärkning

QC 20160518

Tillgänglig från: 2016-05-18 Skapad: 2016-05-18 Senast uppdaterad: 2016-05-20Bibliografiskt granskad

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Yoluk, ÖzgeLindahl, Erik

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Yoluk, ÖzgeBrömstrup, TorbenLindahl, Erik
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BeräkningsbiofysikScience for Life Laboratory, SciLifeLabSeRC - Swedish e-Science Research Centre
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Biophysical Journal
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Totalt: 87 träffar
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