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Assessment of homology templates and an anesthetic binding site within the ?-aminobutyric acid receptor
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-8354-0253
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-2734-2794
Department of Anesthesia, Stanford University School of Medicine, United States .
2013 (English)In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 119, no 5, 1087-1095 p.Article in journal (Refereed) Published
Abstract [en]

Background: Anesthetics mediate portions of their activity via modulation of the ?-aminobutyric acid receptor (GABAaR). Although its molecular structure remains unknown, significant progress has been made toward understanding its interactions with anesthetics via molecular modeling. Methods: The structure of the torpedo acetylcholine receptor (nAChR?), the structures of the ?4 and ?2 subunits of the human nAChR, the structures of the eukaryotic glutamate-gated chloride channel (GluCl), and the prokaryotic pH-sensing channels, from Gloeobacter violaceus and Erwinia chrysanthemi, were aligned with the SAlign and 3DMA algorithms. A multiple sequence alignment from these structures and those of the GABAaR was performed with ClustalW. The Modeler and Rosetta algorithms independently created three-dimensional constructs of the GABAaR from the GluCl template. The CDocker algorithm docked a congeneric series of propofol derivatives into the binding pocket and scored calculated binding affinities for correlation with known GABAaR potentiation EC50s. Results: Multiple structure alignments of templates revealed a clear consensus of residue locations relevant to anesthetic effects except for torpedo nAChR. Within the GABAaR models generated from GluCl, the residues notable for modulating anesthetic action within transmembrane segments 1, 2, and 3 converged on the intersubunit interface between ? and ? subunits. Docking scores of a propofol derivative series into this binding site showed strong linear correlation with GABAaR potentiation EC50. Conclusion: Consensus structural alignment based on homologous templates revealed an intersubunit anesthetic binding cavity within the transmembrane domain of the GABAaR, which showed a correlation of ligand docking scores with experimentally measured GABAaR potentiation.

Place, publisher, year, edition, pages
2013. Vol. 119, no 5, 1087-1095 p.
Keyword [en]
4 aminobutyric acid receptor, chloride channel, glutamic acid, nicotinic receptor alpha4, nicotinic receptor beta2, propofol, algorithm, analgesic activity, article, binding affinity, consensus, drug binding site, drug effect, drug protein binding, Gloeobacter violaceus, human, molecular docking, molecular model, nonhuman, Pectobacterium chrysanthemi, pH, priority journal, prokaryote, protein structure, sequence alignment
National Category
Biophysics Anesthesiology and Intensive Care
URN: urn:nbn:se:kth:diva-139979DOI: 10.1097/ALN.0b013e31829e47e3ISI: 000329797900015ScopusID: 2-s2.0-84888298803OAI: diva2:689516

QC 20140121

Available from: 2014-01-21 Created: 2014-01-16 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
National Category
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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