Molecular mechanism for the dual alcohol modulation of cys loop receptors
2012 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 8, no 10, e1002710- p.Article in journal (Refereed) Published
Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and gamma-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-mu s 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.
Place, publisher, year, edition, pages
2012. Vol. 8, no 10, e1002710- p.
Biochemistry and Molecular Biology Bioinformatics (Computational Biology)
IdentifiersURN: urn:nbn:se:su:diva-83992DOI: 10.1371/journal.pcbi.1002710ISI: 000310568800011OAI: oai:DiVA.org:su-83992DiVA: diva2:577951