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

Tan, Kelly R; Baur, Roland; Charon, Sébastien; Goeldner, Maurice; Sigel, Erwin (2009). Relative positioning of diazepam in the benzodiazepine-binding-pocket of GABA receptors. Journal of neurochemistry, 111(5), pp. 1264-73. Oxford: Wiley-Blackwell 10.1111/j.1471-4159.2009.06419.x

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Baur, Roland and Sigel, Erwin

ISSN:

0022-3042

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:12

Last Modified:

04 May 2014 23:23

Publisher DOI:

10.1111/j.1471-4159.2009.06419.x

PubMed ID:

19804380

Web of Science ID:

000271496500017

URI:

https://boris.unibe.ch/id/eprint/31632 (FactScience: 196263)

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