Document Type
Article
Publication Date
12-7-2017
Abstract
Small-conductance Ca2+-activated K+ (SK) channels play essential roles in the regulation of cellular excitability and have been implicated in neurological and cardiovascular diseases through both animal model studies and human genetic association studies. Over the past two decades, positive modulators of SK channels such as NS309 and 1-EBIO have been developed. Our previous structural studies have identified the binding pocket of 1-EBIO and NS309 that is located at the interface between the channel and calmodulin. In this study, we took advantage of four compounds with potencies varying over three orders of magnitude, including 1-EBIO, NS309, SKS-11 (6-bromo-5-methyl-1H-indole-2,3-dione-3-oxime) and SKS-14 (7-fluoro-3-(hydroxyimino)indolin-2-one). A combination of x-ray crystallographic, computational and electrophysiological approaches was utilized to investigate the interactions between the positive modulators and their binding pocket. A strong trend exists between the interaction energy of the compounds within their binding site calculated from the crystal structures, and the potency of these compounds in potentiating the SK2 channel current determined by electrophysiological recordings. Our results further reveal that the difference in potency of the positive modulators in potentiating SK2 channel activity may be attributed primarily to specific electrostatic interactions between the modulators and their binding pocket.
Recommended Citation
Nam Y-W, Orfali R, Liu T, et al. Structural insights into the potency of SK channel positive modulators. Sci Rep. 2017;7(1):17178. doi:10.1038/s41598-017-16607-8.
Copyright
The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Animal Experimentation and Research Commons, Cardiology Commons, Cardiovascular Diseases Commons, Cell Biology Commons, Nervous System Diseases Commons, Neurology Commons, Neurosciences Commons, Other Pharmacy and Pharmaceutical Sciences Commons
Comments
This article was originally published in Scientific Reports, volume 7, issue 1, in 2017. DOI: 10.1038/s41598-017-16607-8