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dc.creatorMurail, Samuelen
dc.creatorHoward, Rebecca J.en
dc.creatorBroemstrup, Torbenen
dc.creatorBertaccini, Edward J.en
dc.creatorHarris, R. Adronen
dc.creatorTrudell, James R.en
dc.creatorLindahl, Eriken
dc.date.accessioned2013-06-28T15:58:07Zen
dc.date.available2013-06-28T15:58:07Zen
dc.date.issued2012-10-04en
dc.identifier.citationMurail S, Howard RJ, Broemstrup T, Bertaccini EJ, Harris RA, et al. (2012) Molecular Mechanism for the Dual Alcohol Modulation of Cys-loop Receptors. PLoS Comput Biol 8(10): e1002710. doi:10.1371/journal.pcbi.1002710en
dc.identifier.urihttp://hdl.handle.net/2152/20563en
dc.descriptionSamuel Murail is with Stockholm University, Rebecca J. Howard is with UT Austin, Torben Broemstrup is with Stockholm University, Edward J. Bertaccini is with the Palo Alto Veterans Affairs Health Care System and Stanford University School of Medicine, R. Adron Harris is with UT Austin, James R. Trudell is with Stanford University School of Medicine, Erik Lindahl is with Stockholm University.en
dc.description.abstractCys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and γ-aminobutyric acid. Several bacterial homologues have been identified that are excellent models for understanding allosteric binding of alcohols and anesthetics in human Cys-loop receptors. Recently, we showed that a single point mutation on a prokaryotic homologue (GLIC) could transform it from a channel weakly potentiated by ethanol into a highly ethanol-sensitive channel. Here, we have employed molecular simulations to study ethanol binding to GLIC, and to elucidate the role of the ethanol-enhancing mutation in GLIC modulation. By performing 1-µs simulations with and without ethanol on wild-type and mutated GLIC, we observed spontaneous binding in both intra-subunit and inter-subunit transmembrane cavities. In contrast to the glycine receptor GlyR, in which we previously observed ethanol binding primarily in an inter-subunit cavity, ethanol primarily occupied an intra-subunit cavity in wild-type GLIC. However, the highly ethanol-sensitive GLIC mutation significantly enhanced ethanol binding in the inter-subunit cavity. These results demonstrate dramatic effects of the F(14′)A mutation on the distribution of ligands, and are consistent with a two-site model of pLGIC inhibition and potentiation.en
dc.description.sponsorshipThis work was supported by grants from the Swedish Research Council (2010-491,2010-5107), the European Research Council (209825), the Swedish Foundation for Strategic Research, the Swedish e-Science Research Center, National Institutes of Health/National Institutes on Alcohol Abuse and Alcoholism Grants T32 AA007471, R01 AA06399, and R01 AA013378. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.language.isoengen
dc.publisherPublic Library of Scienceen
dc.rightsAttribution 3.0 United Statesen
dc.rightsCC-BYen
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/en
dc.subjectAlcoholsen
dc.subjectAnestheticsen
dc.subjectBiochemical simulationsen
dc.subjectCrystal structureen
dc.subjectEthanolen
dc.subjectLigand-gated ion channelsen
dc.subjectMutationen
dc.subjectNicotinic acetylcholine receptorsen
dc.titleMolecular Mechanism for the Dual Alcohol Modulation of Cys-loop Receptorsen
dc.typeArticleen
dc.description.departmentWaggoner Center for Alcohol and Addiction Researchen
dc.identifier.doi10.1371/journal.pcbi.1002710en


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Attribution 3.0 United States
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