Assessment of homology templates and an anesthetic binding site within the ?-aminobutyric acid receptor
2013 (English)In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 119, no 5, 1087-1095 p.Article in journal (Refereed) Published
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.
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
Biophysics Anesthesiology and Intensive Care
IdentifiersURN: urn:nbn:se:kth:diva-139979DOI: 10.1097/ALN.0b013e31829e47e3ISI: 000329797900015ScopusID: 2-s2.0-84888298803OAI: oai:DiVA.org:kth-139979DiVA: diva2:689516
QC 201401212014-01-212014-01-162016-05-18Bibliographically approved