New insights into the GABAA receptor structure and orthosteric ligand binding: Receptor modeling guided by experimental data

Tommy Sander; Bente Flensborg Frølund; Anne Techau Bruun; Ivaylo Ivanov; James Andrew McCammon; Thomas Balle

doi:10.1002/prot.22975

New insights into the GABA_A receptor structure and orthosteric ligand binding: Receptor modeling guided by experimental data

Tommy Sander, Bente Flensborg Frølund, Anne Techau Bruun, Ivaylo Ivanov, James Andrew McCammon, Thomas Balle

34 Citationer (Scopus)

Abstract

GABA _A receptors (GABA _ARs) are ligand gated chloride ion channels that mediate overall inhibitory signaling in the CNS. A detailed understanding of their structure is important to gain insights in, e.g., ligand binding and functional properties of this pharmaceutically important target. Homology modeling is a necessary tool in this regard because experimentally determined structures are lacking. Here we present an exhaustive approach for creating a high quality model of the α ₁β ₂γ ₂ subtype of the GABA _AR ligand binding domain, and we demonstrate its usefulness in understanding details of orthosteric ligand binding. The model was constructed by using multiple templates and by incorporation of knowledge from biochemical/pharmacological experiments. It was validated on the basis of objective energy functions, its ability to account for available residue specific information, and its stability in molecular dynamics (MD) compared with that of the two homologous crystal structures. We then combined the model with extensive structure-activity relationships available from two homologous series of orthosteric GABA _AR antagonists to create a detailed hypothesis for their binding modes. Excellent agreement with key experimental data was found, including the ability of the model to accommodate and explain a previously developed pharmacophore model. A coupling to agonist binding was thereby established and discussed in relation to activation mechanisms. Our results highlight the importance of critical evaluation and optimization of each step in the homology modeling process. The approach taken here can greatly aid in increasing the understanding of GABA _ARs and related receptors where structural insight is limited and reliable models are difficult to obtain.

Originalsprog	Engelsk
Tidsskrift	Proteins: Structure, Function, and Bioinformatics
Vol/bind	79
Udgave nummer	5
Sider (fra-til)	1458-1477
ISSN	0887-3585
DOI	https://doi.org/10.1002/prot.22975
Status	Udgivet - maj 2011

Emneord

Det tidligere Farmaceutiske Fakultet

Adgang til dokumentet

10.1002/prot.22975

Citationsformater

New insights into the GABA_A receptor structure and orthosteric ligand binding : Receptor modeling guided by experimental data. / Sander, Tommy; Frølund, Bente Flensborg; Bruun, Anne Techau et al.

I: Proteins: Structure, Function, and Bioinformatics, Bind 79, Nr. 5, 05.2011, s. 1458-1477.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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abstract = "GABA A receptors (GABA ARs) are ligand gated chloride ion channels that mediate overall inhibitory signaling in the CNS. A detailed understanding of their structure is important to gain insights in, e.g., ligand binding and functional properties of this pharmaceutically important target. Homology modeling is a necessary tool in this regard because experimentally determined structures are lacking. Here we present an exhaustive approach for creating a high quality model of the α 1β 2γ 2 subtype of the GABA AR ligand binding domain, and we demonstrate its usefulness in understanding details of orthosteric ligand binding. The model was constructed by using multiple templates and by incorporation of knowledge from biochemical/pharmacological experiments. It was validated on the basis of objective energy functions, its ability to account for available residue specific information, and its stability in molecular dynamics (MD) compared with that of the two homologous crystal structures. We then combined the model with extensive structure-activity relationships available from two homologous series of orthosteric GABA AR antagonists to create a detailed hypothesis for their binding modes. Excellent agreement with key experimental data was found, including the ability of the model to accommodate and explain a previously developed pharmacophore model. A coupling to agonist binding was thereby established and discussed in relation to activation mechanisms. Our results highlight the importance of critical evaluation and optimization of each step in the homology modeling process. The approach taken here can greatly aid in increasing the understanding of GABA ARs and related receptors where structural insight is limited and reliable models are difficult to obtain.",

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author = "Tommy Sander and Fr{\o}lund, {Bente Flensborg} and Bruun, {Anne Techau} and Ivaylo Ivanov and McCammon, {James Andrew} and Thomas Balle",

note = "Keywords: homology modeling, spatial restraints, molecular dynamics, ligand docking, GRID analysis, 5-(4-piperidyl)-3-isoxazolol, 4-(4-piperidyl)-1-hydroxypyrazole, 4-PIOL, 4-PHP",

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AU - Ivanov, Ivaylo

AU - McCammon, James Andrew

AU - Balle, Thomas

N1 - Keywords: homology modeling, spatial restraints, molecular dynamics, ligand docking, GRID analysis, 5-(4-piperidyl)-3-isoxazolol, 4-(4-piperidyl)-1-hydroxypyrazole, 4-PIOL, 4-PHP

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N2 - GABA A receptors (GABA ARs) are ligand gated chloride ion channels that mediate overall inhibitory signaling in the CNS. A detailed understanding of their structure is important to gain insights in, e.g., ligand binding and functional properties of this pharmaceutically important target. Homology modeling is a necessary tool in this regard because experimentally determined structures are lacking. Here we present an exhaustive approach for creating a high quality model of the α 1β 2γ 2 subtype of the GABA AR ligand binding domain, and we demonstrate its usefulness in understanding details of orthosteric ligand binding. The model was constructed by using multiple templates and by incorporation of knowledge from biochemical/pharmacological experiments. It was validated on the basis of objective energy functions, its ability to account for available residue specific information, and its stability in molecular dynamics (MD) compared with that of the two homologous crystal structures. We then combined the model with extensive structure-activity relationships available from two homologous series of orthosteric GABA AR antagonists to create a detailed hypothesis for their binding modes. Excellent agreement with key experimental data was found, including the ability of the model to accommodate and explain a previously developed pharmacophore model. A coupling to agonist binding was thereby established and discussed in relation to activation mechanisms. Our results highlight the importance of critical evaluation and optimization of each step in the homology modeling process. The approach taken here can greatly aid in increasing the understanding of GABA ARs and related receptors where structural insight is limited and reliable models are difficult to obtain.

AB - GABA A receptors (GABA ARs) are ligand gated chloride ion channels that mediate overall inhibitory signaling in the CNS. A detailed understanding of their structure is important to gain insights in, e.g., ligand binding and functional properties of this pharmaceutically important target. Homology modeling is a necessary tool in this regard because experimentally determined structures are lacking. Here we present an exhaustive approach for creating a high quality model of the α 1β 2γ 2 subtype of the GABA AR ligand binding domain, and we demonstrate its usefulness in understanding details of orthosteric ligand binding. The model was constructed by using multiple templates and by incorporation of knowledge from biochemical/pharmacological experiments. It was validated on the basis of objective energy functions, its ability to account for available residue specific information, and its stability in molecular dynamics (MD) compared with that of the two homologous crystal structures. We then combined the model with extensive structure-activity relationships available from two homologous series of orthosteric GABA AR antagonists to create a detailed hypothesis for their binding modes. Excellent agreement with key experimental data was found, including the ability of the model to accommodate and explain a previously developed pharmacophore model. A coupling to agonist binding was thereby established and discussed in relation to activation mechanisms. Our results highlight the importance of critical evaluation and optimization of each step in the homology modeling process. The approach taken here can greatly aid in increasing the understanding of GABA ARs and related receptors where structural insight is limited and reliable models are difficult to obtain.

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