Microsecond Simulations Indicate that Ethanol Binds between Subunits and Could Stabilize an Open-State Model of a Glycine Receptor
2011 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 7, 1642-1650 p.Article in journal (Refereed) Published
Cys-loop receptors constitute a superfamily of ion channels gated by ligands such as acetylcholine, serotonin, glycine, and gamma-aminobutyric acid. All of these receptors are thought to share structural characteristics, but due to high sequence variation and limited structure availability, our knowledge about allosteric binding sites is still limited. These sites are frequent targets of anesthetic and alcohol molecules, and are of high pharmacological importance. We used molecular simulations to study ethanol binding and equilibrium exchange for the homomeric alpha 1 glycine receptor (GlyR alpha 1), modeled on the structure of the Gloeobacter violaceus pentameric ligand-gated channel. Ethanol has a well-known potentiating effect and can be used in high concentrations. By performing two microsecond-scale simulations of GlyR with/without ethanol, we were able to observe spontaneous binding in cavities and equilibrium ligand exchange. Of interest, it appears that there are ethanol-binding sites both between and within the GlyR transmembrane subunits, with the intersubunit site having the highest occupancy and slowest exchange (similar to 200 ns). This model site involves several residues that were previously identified via mutations as being crucial for potentiation. Finally, ethanol appears to stabilize the GlyR model built on a presumably open form of the ligand-gated channel. This stabilization could help explain the effects of allosteric ligand binding in Cys-loop receptors.
Place, publisher, year, edition, pages
Cell Press , 2011. Vol. 100, no 7, 1642-1650 p.
Biophysics Theoretical Chemistry Bioinformatics and Systems Biology
Research subject SRA - E-Science (SeRC)
IdentifiersURN: urn:nbn:se:kth:diva-33241DOI: 10.1016/j.bpj.2011.02.032ISI: 000289494200009ScopusID: 2-s2.0-79959652664OAI: oai:DiVA.org:kth-33241DiVA: diva2:419833
FunderSwedish e‐Science Research Center
QC 201105302011-05-302011-05-022016-04-28Bibliographically approved