Referenced in: none

Automatically associated channels: KChIP1 , Kv1.4 , Kv3.1 , Kv4.2 , Kv4.3

Title: Identification and characterization of small molecule modulators of KChIP/Kv4 function.

Authors: Mark R Bowlby, Pranab Chanda, Wade Edris, Joseph Hinson, Flora Jow, Alan H Katz, Jeffrey Kennedy, Girija Krishnamurthy, Keith Pitts, Kevin Ryan, Howard Zhang, Lynne Greenblatt

Journal, date & volume: Bioorg. Med. Chem., 2005 Nov 15 , 13, 6112-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16081294

Abstract
Potassium channels and their associated subunits are important contributors to electrical excitability in many cell types. In this study, a yeast two-hybrid assay was used to identify inhibitors such as a diaryl-urea compound (CL-888) that binds to and modulates the formation of the Kv4/KChIP complex. CL-888 altered the apparent affinity of KChIP1 to Kv4.3-N in a Biacore assay, but did not dissociate the two proteins in size-exclusion chromatography experiments. Kv4.2/KChIP1 current amplitude and kinetics were altered with compound exposure, supporting the hypothesis of a compound-induced conformational change in the protein complex. Fluorescence spectroscopy of a unique tryptophan residue in KChIP1 was consistent with compound binding to the protein. Molecular modeling using the KChIP1 crystal structure indicates that compound binding may occur in a small tryptophan-containing binding pocket located on the hydrophilic side of the protein.