Structure-guided topographic mapping and mutagenesis to elucidate binding sites for the human ether-a-go-go-related gene 1 potassium channel (KCNH2) activator NS1643

The Journal of Pharmacology and Experimental Therapeutics
Serdar DurdagiHenry J Duff

Abstract

Loss-of -function mutations in human ether-a-go-go-related gene 1 (hERG1) is associated with life-threatening arrhythmias. hERG1 activators are being developed as treatments for acquired or genetic forms of long QT syndrome. The locations of the putative binding pockets for activators are still being elucidated. In silico docking of the activator 1,3-bis-(2-hydroxy-5-trifluoromethylphenyl)-urea (NS1643) to an S1-S6 transmembrane homology model of hERG1 predicted putative binding sites. The predictions of the in silico docking guided subsequent in vitro mutagenesis and electrophysiological measurements. The novel interacting site for NS1643 is predicted around Asn629 at the outer mouth of the channel. The applied N629H mutation is the sole amino acid replacement in the literature that abrogates the NS1643-induced left shift of the V(1/2) of activation. In contrast, both N629T and N629D showed pharmacologic responses similar to wild type. Another important interacting pocket is predicted at the intracellular surface in the S4-S5 linker. Mutagenesis of the residues critical to interactions in this pocket had major effects on the pharmacologic response to NS1643. The inward conductance elicited by hyperpolarization of D540K hERG1 w...Continue Reading

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Citations

Dec 12, 2012·PloS One·Arne Bilet, Christiane K Bauer
Apr 9, 2013·Journal of Enzyme Inhibition and Medicinal Chemistry·N S Hari Narayana MoorthyPedro A Fernandes
Jun 18, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Ramin Ekhteiari SalmasSerdar Durdagi
Mar 6, 2015·Proteins·James D Alsop, Julie C Mitchell
May 5, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Ali ŞahinMert Mestanoğlu
Jul 26, 2017·Clinical and Experimental Pharmacology & Physiology·JianHua HuoAiqun Ma
May 1, 2018·Frontiers in Physiology·Laura L PerissinottiSergei Y Noskov
Sep 19, 2014·The Journal of Pharmacology and Experimental Therapeutics·Ping LiZhaobing Gao
Dec 27, 2019·Journal of Chemical Information and Modeling·Eva-Maria Zangerl-PlesslAnna Stary-Weinzinger

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