Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor

Younes Mokrab, Vassiliy N. Bavro, Kenji Mizuguchi, N. P. Todorov, Ian L. Martin, Susan M J Dunn, S. L. Chan, P. L. Chau

Research output: Contribution to journalArticle

Abstract

We present two comparative models of the GABAA receptor. Model 1 is based on the 4-Å 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 GABAA receptor not previously addressed.

Original languageEnglish
Pages (from-to)760-774
Number of pages15
JournalJournal of Molecular Graphics and Modelling
Volume26
Issue number4
DOIs
Publication statusPublished - 1 Nov 2007

Fingerprint

GABA-A Receptors
Ligands
Ions
ligands
ions
acetylcholine
Nicotinic Receptors
torpedoes
GABA Agonists
Alprazolam
commonality
proteins
Proteins
anesthetics
Flunitrazepam
Anesthetics
General Anesthetics
Muscimol
Halothane
Benzodiazepines

Keywords

  • Alprazolam
  • Benzodiazepine
  • Comparative modelling
  • Docking
  • Flunitrazepam
  • GABA
  • GABA receptor
  • Halothane
  • Ligand-gated ion channels (LGIC)
  • Muscimol

Cite this

Mokrab, Y., Bavro, V. N., Mizuguchi, K., Todorov, N. P., Martin, I. L., Dunn, S. M. J., ... Chau, P. L. (2007). Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor. Journal of Molecular Graphics and Modelling , 26(4), 760-774. https://doi.org/10.1016/j.jmgm.2007.04.012
Mokrab, Younes ; Bavro, Vassiliy N. ; Mizuguchi, Kenji ; Todorov, N. P. ; Martin, Ian L. ; Dunn, Susan M J ; Chan, S. L. ; Chau, P. L. / Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor. In: Journal of Molecular Graphics and Modelling . 2007 ; Vol. 26, No. 4. pp. 760-774.
@article{a84308687c02427eb20a1e3b2e718102,
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 GABAA receptor. Model 1 is based on the 4-{\AA} 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 GABAA receptor not previously addressed.",
keywords = "Alprazolam, Benzodiazepine, Comparative modelling, Docking, Flunitrazepam, GABA, GABA receptor, Halothane, Ligand-gated ion channels (LGIC), Muscimol",
author = "Younes Mokrab and Bavro, {Vassiliy N.} and Kenji Mizuguchi and Todorov, {N. P.} and Martin, {Ian L.} and Dunn, {Susan M J} and Chan, {S. L.} and Chau, {P. L.}",
year = "2007",
month = "11",
day = "1",
doi = "10.1016/j.jmgm.2007.04.012",
language = "English",
volume = "26",
pages = "760--774",
journal = "Journal of Molecular Graphics and Modelling",
issn = "1093-3263",
publisher = "Elsevier",
number = "4",

}

Mokrab, Y, Bavro, VN, Mizuguchi, K, Todorov, NP, Martin, IL, Dunn, SMJ, Chan, SL & Chau, PL 2007, 'Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor', Journal of Molecular Graphics and Modelling , vol. 26, no. 4, pp. 760-774. https://doi.org/10.1016/j.jmgm.2007.04.012

Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor. / Mokrab, Younes; Bavro, Vassiliy N.; Mizuguchi, Kenji; Todorov, N. P.; Martin, Ian L.; Dunn, Susan M J; Chan, S. L.; Chau, P. L.

In: Journal of Molecular Graphics and Modelling , Vol. 26, No. 4, 01.11.2007, p. 760-774.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor

AU - Mokrab, Younes

AU - Bavro, Vassiliy N.

AU - Mizuguchi, Kenji

AU - Todorov, N. P.

AU - Martin, Ian L.

AU - Dunn, Susan M J

AU - Chan, S. L.

AU - Chau, P. L.

PY - 2007/11/1

Y1 - 2007/11/1

N2 - We present two comparative models of the GABAA receptor. Model 1 is based on the 4-Å 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 GABAA receptor not previously addressed.

AB - We present two comparative models of the GABAA receptor. Model 1 is based on the 4-Å 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 GABAA receptor not previously addressed.

KW - Alprazolam

KW - Benzodiazepine

KW - Comparative modelling

KW - Docking

KW - Flunitrazepam

KW - GABA

KW - GABA receptor

KW - Halothane

KW - Ligand-gated ion channels (LGIC)

KW - Muscimol

UR - http://www.scopus.com/inward/record.url?scp=35448998854&partnerID=8YFLogxK

U2 - 10.1016/j.jmgm.2007.04.012

DO - 10.1016/j.jmgm.2007.04.012

M3 - Article

VL - 26

SP - 760

EP - 774

JO - Journal of Molecular Graphics and Modelling

JF - Journal of Molecular Graphics and Modelling

SN - 1093-3263

IS - 4

ER -