Determination of binding site residues responsible for the subunit selectivity of novel marine-derived compounds on kainate receptors

Molecular Pharmacology
James M SandersGeoffrey T Swanson

Abstract

Dysiherbaine (DH) and related molecules are high-affinity, subunit-selective kainate receptor (KAR) ligands originally isolated from a marine sponge. To elucidate why DH, an agonist, and MSVIII-19, a competitive antagonist, bind selectively to glutamate receptor (GluR) 5 but not to the KA2 KAR subunit, we used molecular dynamics simulations to generate binding models that were tested experimentally in radioligand binding and electrophysiological assays. Three candidate sites, Val685, Leu735, and Ser741 in GluR5, corresponding to Ile669, Phe719, and Met725 in KA2, were predicted to underlie the distinct binding profiles of the marine toxins. Single or multiple reciprocal mutations introduced into the receptor subunits produced a variety of effects on binding affinity. Most notably, mutation of Met725 to serine in KA2 increased the affinity of DH by 350-fold; in contrast, mutation of one or more of the residues in GluR5 did not markedly alter DH binding. MSVIII-19 affinity for the KA2 subunit was significantly increased in multiple site mutants, and reciprocal mutations in the GluR5 subunit produced substantial (700-fold) reductions in MSVIII-19 affinity. Physiological characterization of the double- and triple-mutant subunits de...Continue Reading

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Citations

Apr 20, 2011·Journal of Chemical Information and Modeling·Pekka A PostilaOlli T Pentikäinen
Oct 11, 2007·Chemical Communications : Chem Comm·Keisuke TakahashiSusumi Hatakeyama
Nov 23, 2007·The Journal of Pharmacology and Experimental Therapeutics·L Leanne LashGeoffrey T Swanson
Dec 23, 2009·The Journal of Physiology·David D MottMorris Benveniste
Sep 10, 2009·Neuropharmacology·Pekka A PostilaOlli T Pentikäinen
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Dec 7, 2007·The Journal of Organic Chemistry·Makoto SasakiKeiko Shimamoto
Nov 3, 2007·The Journal of Organic Chemistry·Jamie L Cohen, A Richard Chamberlin

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