Modeling anesthetic binding sites within the glycine alpha one receptor based on prokaryotic ion channel templates: the problem with TM4.
Ligand-gated ion channels (LGICs) significantly modulate anesthetic effects. Their exact molecular structure remains unknown. This has led to ambiguity regarding the proper amino acid alignment within their 3D structure and, in turn, the location of any anesthetic binding sites. Current controversies suggest that such a site could be located in either an intra- or intersubunit locale within the transmembrane domain of the protein. Here, we built a model of the glycine alpha one receptor (GlyRa1) based on the open-state structures of two new high-resolution ion channel templates from the prokaryote, Gloebacter violaceus (GLIC). Sequence scoring suggests reasonable homology between GlyRa1 and GLIC. Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3): (ILE229, SER 267, and ALA 288). They line an intersubunit interface, in contrast to previous models. However, residues from the fourth transmembrane domain (TM4) that are known to modulate a variety of anesthetic effects are quite distant from this putative anesthetic binding site. While this model can account for a large proportion of the physicochemical data regarding such proteins, it cannot readily account for the alterations on anesthetic effects that are due to mutations within TM4.
Department of Anesthesia, Stanford University School of Medicine and Beckman Center for Molecular and Genetic Medicine, Stanford, California, United States. edwardb@stanford.edu
Edward J
EJ
Bertaccini
Björn
B
Wallner
James R
JR
Trudell
Erik
E
Lindahl
D000595:Amino Acid Sequence; D000777:Anesthetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002462:Cell Membrane; D000458:Cyanobacteria; D058446:Ligand-Gated Ion Channels / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D018009:Receptors, Glycine / Q000737:chemistry* / Q000378:metabolism
D000777:Anesthetics; D001426:Bacterial Proteins; D058446:Ligand-Gated Ion Channels; D018009:Receptors, Glycine