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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Standard

New insights into the GABAA receptor structure and orthosteric ligand binding : Receptor modeling guided by experimental data. / Sander, Tommy; Frølund, Bente Flensborg; Bruun, Anne Techau; Ivanov, Ivaylo; McCammon, James Andrew; Balle, Thomas.

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Sander, T, Frølund, BF, Bruun, AT, Ivanov, I, McCammon, JA & Balle, T 2011, 'New insights into the GABAA receptor structure and orthosteric ligand binding: Receptor modeling guided by experimental data', Proteins: Structure, Function, and Bioinformatics, bind 79, nr. 5, s. 1458-1477. https://doi.org/10.1002/prot.22975

APA

Sander, T., Frølund, B. F., Bruun, A. T., Ivanov, I., McCammon, J. A., & Balle, T. (2011). New insights into the GABAA receptor structure and orthosteric ligand binding: Receptor modeling guided by experimental data. Proteins: Structure, Function, and Bioinformatics, 79(5), 1458-1477. https://doi.org/10.1002/prot.22975

Vancouver

Sander T, Frølund BF, Bruun AT, Ivanov I, McCammon JA, Balle T. New insights into the GABAA receptor structure and orthosteric ligand binding: Receptor modeling guided by experimental data. Proteins: Structure, Function, and Bioinformatics. 2011 maj;79(5):1458-1477. https://doi.org/10.1002/prot.22975

Author

Sander, Tommy ; Frølund, Bente Flensborg ; Bruun, Anne Techau ; Ivanov, Ivaylo ; McCammon, James Andrew ; Balle, Thomas. / New insights into the GABAA receptor structure and orthosteric ligand binding : Receptor modeling guided by experimental data. I: Proteins: Structure, Function, and Bioinformatics. 2011 ; Bind 79, Nr. 5. s. 1458-1477.

Bibtex

@article{d5e9ce22d5f34af7a281ec64ed679a4c,
title = "New insights into the GABAA receptor structure and orthosteric ligand binding: Receptor modeling guided by experimental data",
abstract = "GABA(A) receptors (GABA(A) Rs) 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 a(1) {\ss}(2) ¿(2) subtype of the GABA(A) R 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(A) R 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(A) Rs and related receptors where structural insight is limited and reliable models are difficult to obtain. Proteins 2011; {\circledC} 2011 Wiley-Liss, Inc.",
keywords = "Former Faculty of Pharmaceutical Sciences",
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",
year = "2011",
month = "5",
doi = "10.1002/prot.22975",
language = "English",
volume = "79",
pages = "1458--1477",
journal = "Proteins: Structure, Function, and Bioinformatics",
issn = "0887-3585",
publisher = "JohnWiley & Sons, Inc.",
number = "5",

}

RIS

TY - JOUR

T1 - New insights into the GABAA receptor structure and orthosteric ligand binding

T2 - Receptor modeling guided by experimental data

AU - Sander, Tommy

AU - Frølund, Bente Flensborg

AU - Bruun, Anne Techau

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

PY - 2011/5

Y1 - 2011/5

N2 - GABA(A) receptors (GABA(A) Rs) 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 a(1) ß(2) ¿(2) subtype of the GABA(A) R 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(A) R 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(A) Rs and related receptors where structural insight is limited and reliable models are difficult to obtain. Proteins 2011; © 2011 Wiley-Liss, Inc.

AB - GABA(A) receptors (GABA(A) Rs) 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 a(1) ß(2) ¿(2) subtype of the GABA(A) R 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(A) R 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(A) Rs and related receptors where structural insight is limited and reliable models are difficult to obtain. Proteins 2011; © 2011 Wiley-Liss, Inc.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1002/prot.22975

DO - 10.1002/prot.22975

M3 - Journal article

C2 - 21365676

VL - 79

SP - 1458

EP - 1477

JO - Proteins: Structure, Function, and Bioinformatics

JF - Proteins: Structure, Function, and Bioinformatics

SN - 0887-3585

IS - 5

ER -

ID: 33170846