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Relative positioning of diazepam in the benzodiazepine-binding-pocket of GABA receptors

Tan, Kelly R. and Baur, Roland and Charon, Sébastien and Goeldner, Maurice and Sigel, Erwin. (2009) Relative positioning of diazepam in the benzodiazepine-binding-pocket of GABA receptors. Journal of Neurochemistry, 111 (5). pp. 1264-1273.

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Official URL: http://edoc.unibas.ch/50652/

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Abstract

GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain. Some of them are targets of benzodiazepines that are widely used in clinical practice for their sedative/hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects. In order to rationally separate these different drug actions, we need to understand the interaction of such compounds with the benzodiazepine-binding pocket. With this aim, we mutated residues located in the benzodiazepine-binding site individually to cysteine. These mutated receptors were combined with benzodiazepine site ligands carrying a cysteine reactive group in a defined position. Proximal apposition of reaction partners will lead to a covalent reaction. We describe here such proximity-accelerated chemical coupling reactions of alpha(1)S205C and alpha(1)T206C with a diazepam derivative modified at the C-3 position with a reactive isothiocyanate group (-NCS). We also provide new data that identify alpha(1)H101C and alpha(1)N102C as exclusive sites of the reaction of a diazepam derivative where the -Cl atom is replaced by a -NCS group. Based on these observations we propose a relative positioning of diazepam within the benzodiazepine-binding site of alpha(1)beta(2)gamma(2) receptors.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Physiopathology of basal ganglia neuronal subcircuits (Tan)
UniBasel Contributors:Tan, Kelly
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley-Blackwell
ISSN:0022-3042
e-ISSN:1471-4159
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:29 Nov 2017 08:17
Deposited On:29 Nov 2017 08:17

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