Molecular modeling and mutagenesis reveals a tetradentate binding site for Zn2+ in GABA(A) alphabeta receptors and provides a structural basis for the modulating effect of the gamma subunit

Journal of Chemical Information and Modeling
James R TrudellNeil L Harrison

Abstract

Gamma-aminobutyric acid type A receptors (GABA(A)-R) containing alpha1beta2gamma2 subunits are weakly inhibited by Zn2+, whereas receptors containing only the alpha1beta2 subunits are strongly inhibited. We built homology models of the ion pores of alpha1beta2 and alpha1beta2gamma2 GABA(A)-R using coordinates of the nicotinic acetylcholine receptor as a template. Threading the GABA(A)-R beta2 sequence onto this template placed the 17' histidine and the 20' glutamate residues at adjacent locations in the mouth of the pore, such that a nearly ideal tetradentate site for Zn2+ was formed from two histidine and two glutamate residues between adjacent beta subunits in the alpha1beta2 GABA(A)-R. Following optimization with CHARMM, the distance between the alpha-carbons of the adjacent histidine residues was approximately 9.2 A, close to the ideal distance for a Zn2+ binding site. Loss of inhibition by Zn2+ in alpha1beta2gamma2 GABA(A)-R can be explained by the geometry of these residues in the arrangement alpha1beta2gamma2alpha1beta2, in which the nearest C-alpha-C-alpha distance between the histidine residues is 15.5 A, too far apart for an energetically optimal Zn2+ binding site. We then mutated the gamma subunit at the 17' and/or 2...Continue Reading

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Citations

Aug 18, 2010·ACS Chemical Neuroscience·Edward J BertacciniErik Lindahl
Nov 11, 2011·The Journal of Pharmacology and Experimental Therapeutics·W David JohnsonR Adron Harris
Apr 8, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Andrew J BoileauCynthia Czajkowski
Jun 1, 2012·Expert Opinion on Drug Discovery·Matthew D Krasowski, Anton J Hopfinger
Aug 12, 2010·Pharmaceuticals·Yongchang ChangPaul Whiteaker
Nov 22, 2018·Pharmacology Research & Perspectives·Olivia A Moody, Andrew Jenkins
Nov 6, 2015·Molecular Pharmacology·Rogelio O ArellanoCarlos Matute

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