title: Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor.
abstract: We present two comparative models of the GABA(A) receptor. Model 1 is based on the 4-A resolution structure of the nicotinic acetylcholine receptor from Torpedo marmorata and represents the unliganded receptor. Two agonists, GABA and muscimol, two benzodiazepines, flunitrazepam and alprazolam, together with the general anaesthetic halothane, have been docked to this model. The ion flow is also explored in model 1 by evaluating the interaction energy of a chloride ion as it traverses the extracellular, transmembrane and intracellular domains of the protein. Model 2 differs from model 1 only in the extracellular domain and represents the liganded receptor. Comparison between the two models not only allows us to explore commonalities and differences with comparative models of the nicotinic acetylcholine receptor, but also suggests possible protein sub-domain interactions with the GABA(A) receptor not previously addressed.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
authors.forename: Younes
authors.initials: Y
authors.lastname: Mokrab
authors.forename: Vassiliy N
authors.initials: VN
authors.lastname: Bavro
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizuguchi
authors.forename: N P
authors.initials: NP
authors.lastname: Todorov
authors.forename: Ian L
authors.initials: IL
authors.lastname: Martin
authors.forename: Susan M J
authors.initials: SM
authors.lastname: Dunn
authors.forename: S L
authors.initials: SL
authors.lastname: Chan
authors.forename: P-L
authors.initials: PL
authors.lastname: Chau
mesh_terms: D000595:Amino Acid Sequence; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D005445:Flunitrazepam / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009118:Muscimol / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam