Publication: Chromanol 293B Binding in KCNQ1 (Kv7.1) Channels involves Electrostatic Interactions with a Potassium Ion in the Selectivity Filter
All || By Area || By Year| Title | Chromanol 293B Binding in KCNQ1 (Kv7.1) Channels involves Electrostatic Interactions with a Potassium Ion in the Selectivity Filter | Authors/Editors* | Lerche C, Bruhova I, Lerche H, Steinmeyer K, Wei A, Strutz-Seebohm N, Busch AE, Lang F, Zhorov BS, Seebohm G |
|---|---|
| Where published* | Molecular Pharmacology |
| How published* | Journal |
| Year* | 2007 |
| Volume | 71 |
| Number | 6 |
| Pages | 1503-11 |
| Publisher | |
| Keywords | |
| Link | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17347319&query_hl=1&itool=pubmed_docsum |
| Abstract |
The chromanol 293B (293B, trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chroman) is a lead compound of potential class III antiarrhythmics that inhibit cardiac IKs potassium channels. These channels are formed by the coassembly of KCNQ1 (Kv7.1, KvLQT1) and KCNE1 subunits. While homomeric KCNQ1 channels are the principal molecular targets, entry of KCNE1 to the channel complex enhances the chromanol block. Since closely related neuronal KCNQ2 potassium channels are insensitive to the drug, we used KCNQ1/KCNQ2 chimeras to identify the binding site of the inhibitor. We localized the putative drug receptor to the H5 selectivity filter and the S6 transmembrane segment. Single residues affecting 293B inhibition were subsequently identified through systematic exchange of amino acids either differing between KCNQ1 and KCNQ2, or predicted by a docking model of 293B in the open and closed conformation of KCNQ1. Mutant channel proteins T312S, I337V and F340Y displayed dramatically lowered sensitivity to chromanol block. The predicted drug binding receptor lies in the inner pore vestibule containing the lower part of the selectivity filter and the S6 transmembrane domain also reported to be important for binding of benzodiazepines. We propose that the block of the ion permeation pathway involves hydrophobic interactions with the S6 transmembrane residues I337 and F340, and stabilization of chromanol 293B binding through electrostatic interactions of its oxygens with the most internal potassium ion within the selectivity filter. |
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