Comparative Models of GABAA Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Functions⃞

@article{Ernst2005ComparativeMO,
  title={Comparative Models of GABAA Receptor Extracellular and Transmembrane Domains: Important Insights in Pharmacology and Functions⃞},
  author={Margot Ernst and Stefan Bruckner and Stefan Boresch and Werner Sieghart},
  journal={Molecular Pharmacology},
  year={2005},
  volume={68},
  pages={1291 - 1300}
}
Comparative models of the extracellular and transmembrane domains of GABAA receptors in the agonist-free state were generated based on the recently published structures of the nicotinic acetylcholine receptor. The models were validated by computational methods, and their reliability was estimated by analyzing conserved and variable elements of the cys-loop receptor topology. In addition, the methodological limits in the interpretation of such anion channel receptor models are discussed… Expand
View on ASPET
neurocluster-db.meduniwien.ac.at
138 Citations
Highly Influential Citations
7
Background Citations
66
Methods Citations
14
Results Citations
3

138 Citations

Citation Type

Citation Type

Homology modeling of the transmembrane domain of the GABAA receptor
The permeability of ion channels for ions and substances that bind inside the pore depends on the cross-sectional area of the pore. We have constructed models of the closed, open, and desensitized… Expand
New insights into the GABAA receptor structure and orthosteric ligand binding: Receptor modeling guided by experimental data
TLDR
An exhaustive approach for creating a high quality model of the α1β2γ2 subtype of the GABAAR ligand binding domain is presented, and its usefulness in understanding details of orthosteric ligandbinding is demonstrated. Expand
Exploring ligand recognition and ion flow in comparative models of the human GABA type A receptor.
TLDR
Comparison between the two comparative models of the GABA(A) receptor suggests possible protein sub-domain interactions with the neurons of the nicotinic acetylcholine receptor not previously addressed. Expand
A Molecular Basis for Agonist and Antagonist Actions at GABAC Receptors
We modelled the N‐terminal ligand‐binding domain of the ρ1 GABAC receptor based on the Lymnaea stagnalis acetylcholine‐binding protein (L‐AChBP) crystal structure using comparative modelling and… Expand
Modeling neuronal nicotinic and GABA receptors: important interface salt-links and protein dynamics.
TLDR
The changes seen in the simulations suggest that this network of salt-links helps to set limits and specific states for the conformational changes involved in gating of the receptor, and it is hoped that these hypotheses will be tested experimentally in the near future. Expand
Molecular modelling of the GABAA ion channel protein.
TLDR
The final model of the alpha1beta2gamma2 GABAA protein agrees with available experimental data concerning general anaesthetics. Expand
GABAA receptors: Subtypes provide diversity of function and pharmacology
TLDR
This mini-review attempts to update experimental evidence on the existence of GABA(A) receptor pharmacological subtypes and to produce a list of those native receptors that exist and proposes several criteria for including a receptor hetero-oligomeric subtype candidate on a lists of native subtypes, and a working GABA( A) receptor list. Expand
Analysis of γ-Aminobutyric Acid (GABA) Type A Receptor Subtypes Using Isosteric and Allosteric Ligands
  • R. Olsen
  • Chemistry, Medicine
  • Neurochemical Research
  • 2014
TLDR
The channel blocker picrotoxin identified a noncompetitive channel blocker site in GABAARs, which is located in the transmembrane channel pore, whereas the GABA agonist site is in the extracellular domain at subunit interfaces, a site useful for low energy coupled conformational changes of the functional channel domain. Expand
Investigating the Putative Binding-mode of GABA and Diazepam within GABAA Receptor Using Molecular Modeling
TLDR
The three-dimensional structure of the GABAA receptor that included the ligand/agonist binding site was constructed and validated by using molecular modeling technology and seemed to represent the correct orientation of diazepam in the binding site. Expand
Structural models of ligand-gated ion channels: sites of action for anesthetics and ethanol.
TLDR
Amino acid residues necessary for pharmacologically relevant allosteric modulation of LGIC function by anesthetics and EtOH have been identified in these channel proteins. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 49 REFERENCES
Comparative modeling of GABAA receptors: limits, insights, future developments
TLDR
In this commentary, difficulties with comparative modeling at low sequence identity are discussed, the degree of structural conservation to be expected within the superfamily is analyzed and numerical estimates of model uncertainties in functional regions are provided. Expand
GABAA receptor structure-function studies: a reexamination in light of new acetylcholine receptor structures.
  • M. Akabas
  • Chemistry, Medicine
  • International review of neurobiology
  • 2004
TLDR
The chapter provides an overview of the channel's functional properties and discusses the structural bases for these properties and outlines the substituted-cysteine accessibility method (SCAM). Expand
Charged Residues in the β2 Subunit Involved in GABAA Receptor Activation*
TLDR
Interactions between an acidic residue in loop 7 (Asp146) and a basic residue in pre-transmembrane domain-1 (Lys215) are involved in coupling agonist binding to channel gating, and suggest that interactions between these flexible loops within the β2 subunit are involvedIn conclusion, GABAA-R β2 receptor activation is mediated primarily via activation of the γ-aminobutyric acid type A receptor. Expand
Functional and Structural Analysis of the GABAA Receptor α1 Subunit during Channel Gating and Alcohol Modulation*
TLDR
The data show that GABAA receptor is a dynamic protein during alcohol modulation and channel gating, and a conformational change produced by alcohols induces the water cavity around the A291C and Y294C residues to extend deeper, causing the A295C and F296C residue to become accessible to the MTS reagents. Expand
Evaluation of a proposed mechanism of ligand-gated ion channel activation in the GABAA and glycine receptors
Ligand-gated ion channels (LGICs) mediate rapid chemical neurotransmission in the mammalian brain. This gene superfamily includes the nicotinic acetylcholine (nAChR), GABA(A), 5-hydroxytryptamine… Expand
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
  • N. Unwin
  • Chemistry, Medicine
  • Journal of molecular biology
  • 2005
TLDR
A comparison of the structure of the alpha subunit with that of AChBP having ligand present, suggests how the localised rearrangement overcomes the distortions and initiates the rotational movements associated with opening of the channel. Expand
Identification of channel-lining residues in the M2 membrane-spanning segment of the GABA(A) receptor alpha1 subunit
  • M. Xu, M. Akabas
  • Chemistry, Medicine
  • The Journal of general physiology
  • 1996
TLDR
The ability of the positively charged reagent methanethiosulfonate ethylammonium to reach the level of alpha1 Thr261 suggests that the charge-selectivity filter is at least as cytoplasmic as this residue. Expand
Coupling of agonist binding to channel gating in the GABAA receptor
TLDR
It is shown that optimal gating in the GABAA receptor, a member of the LGIC superfamily, is dependent on electrostatic interactions between the negatively charged Asp 57 and Asp 149 residues in extracellular loops 2 and 7, and the positively charged Lys 279 residue in the transmembrane 2–3 linker region of the α1-subunit. Expand
Comparative modeling of a GABAA alpha1 receptor using three crystal structures as templates.
TLDR
The model reveals structures of loops that were not visible in the cryoelectron micrograph and satisfies most labeling and mutagenesis data and suggests mechanisms for ligand binding transduction, ion selectivity, and anesthetic binding. Expand
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors
TLDR
The crystal structure of molluscan acetylcholine-binding protein (AChBP), a structural and functional homologue of the amino-terminal ligand-binding domain of an nAChR α-subunit, is presented and is relevant for the development of drugs against Alzheimer’s disease and nicotine addiction. Expand
...
1
2
3
4
5
...