Homology modeling of a human glycine alpha 1 receptor reveals a plausible anesthetic binding site.
The superfamily of ligand-gated ion channels (LGICs) has been implicated in anesthetic and alcohol responses. Mutations within glycine and GABA receptors have demonstrated that possible sites of anesthetic action exist within the transmembrane subunits of these receptors. The exact molecular arrangement of this transmembrane region remains at intermediate resolution with current experimental techniques. Homology modeling methods were therefore combined with experimental data to produce a more exact model of this region. A consensus from multiple bioinformatics techniques predicted the topology within the transmembrane domain of a glycine alpha one receptor (GlyRa1) to be alpha helical. This fold information was combined with sequence information using the SeqFold algorithm to search for modeling templates. Independently, the FoldMiner algorithm was used to search for templates that had structural folds similar to published coordinates of the homologous nAChR (1OED). Both SeqFold and Foldminer identified the same modeling template. The GlyRa1 sequence was aligned with this template using multiple scoring criteria. Refinement of the alignment closed gaps to produce agreement with labeling studies carried out on the homologous receptors of the superfamily. Structural assignment and refinement was achieved using Modeler. The final structure demonstrated a cavity within the core of a four-helix bundle. Residues known to be involved in modulating anesthetic potency converge on and line this cavity. This suggests that the binding sites for volatile anesthetics in the LGICs are the cavities formed within the core of transmembrane four-helix bundles.
Bertaccini
Edward J
EJ
Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305-5117, USA. edwardb@stanford.edu
Shapiro
Jessica
J
Brutlag
Douglas L
DL
Trudell
James R
JR
D000595:Amino Acid Sequence; D000777:Anesthetics / Q000378:metabolism*; D001665:Binding Sites; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D018009:Receptors, Glycine / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000777:Anesthetics; D018009:Receptors, Glycine