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Molecular modeling of the GABAC receptor ligand-binding domain

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Abstract

We have constructed a molecular model of the ligand-binding domain of the GABAC receptor, which is a member of the Cys-loop ligand-gated ion channel family. The extracellular domains of these receptors share similar sequence homology (20%) with Limnaea acetylcholine-binding protein for which an X-ray crystal structure is available. We used this structure as a template for homology modeling of the GABAC receptor extracellular domain using FUGUE and MODELLER software. FlexX was then used to dock GABA into the receptor ligand-binding site, resulting in three alternative energetically favorable orientations. Residues located no more than 5 Å from the docked GABA were identified for each model; of these, three were found to be common to all models with 14 others present only in certain models. Using data from experimental studies, we propose that the most likely orientation of GABA is with its amine close to Y198, and its carboxylate close to R104. These studies have therefore provided a model of the ligand-binding domain, which will be useful for both GABAC and GABAA receptor studies, and have also yielded an experimentally testable hypothesis of the location of GABA in the binding pocket.

GABA docked into the binding site using FlexX. Orientation 3. Residues shown are those within 5 Å of GABA. H-bonds are shown as green dashed lines

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Abbreviations

LGIC:

Ligand-gated ion channel

ACh:

Acetylcholine

AChBP:

Acetylcholine-binding protein

nAChR:

Nicotinic acetylcholine receptor

SCAM:

Substituted cysteine accessibility method

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Acknowledgments

We thank the Wellcome Trust (SCRL), and the MRC (NLH) for funding. SCRL is a Wellcome Trust Senior Research Fellow in Basic Biomedical Studies. We also thank Dr. David Burke for his contributions in running MODELLER and Dr. Andy Thompson for his assistance in creation of the figures.

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Correspondence to Sarah C.R. Lummis.

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Harrison, N.J., Lummis, S.C. Molecular modeling of the GABAC receptor ligand-binding domain. J Mol Model 12, 317–324 (2006). https://doi.org/10.1007/s00894-005-0034-6

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  • DOI: https://doi.org/10.1007/s00894-005-0034-6

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