Title |
Molecular Mechanism for the Dual Alcohol Modulation of Cys-loop Receptors
|
---|---|
Published in |
PLoS Computational Biology, October 2012
|
DOI | 10.1371/journal.pcbi.1002710 |
Pubmed ID | |
Authors |
Samuel Murail, Rebecca J. Howard, Torben Broemstrup, Edward J. Bertaccini, R. Adron Harris, James R. Trudell, Erik Lindahl |
Abstract |
Cys-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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Chile | 1 | 2% |
United States | 1 | 2% |
Unknown | 40 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 16 | 38% |
Researcher | 7 | 17% |
Student > Master | 5 | 12% |
Student > Bachelor | 4 | 10% |
Student > Doctoral Student | 2 | 5% |
Other | 3 | 7% |
Unknown | 5 | 12% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 15 | 36% |
Chemistry | 7 | 17% |
Biochemistry, Genetics and Molecular Biology | 4 | 10% |
Physics and Astronomy | 3 | 7% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 5% |
Other | 5 | 12% |
Unknown | 6 | 14% |