5wbx
Structural insights into the potency of SK/IK channel positive modulatorsStructural insights into the potency of SK/IK channel positive modulators
Structural highlights
Disease[CALM1_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14. Function[KCNN2_HUMAN] Forms a voltage-independent potassium channel activated by intracellular calcium. Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization. The channel is blocked by apamin. [CALM1_HUMAN] Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).[1] [2] [3] [4] Publication Abstract from PubMedSmall-conductance Ca(2+)-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. Structural insights into the potency of SK channel positive modulators.,Nam YW, Orfali R, Liu T, Yu K, Cui M, Wulff H, Zhang M Sci Rep. 2017 Dec 7;7(1):17178. doi: 10.1038/s41598-017-16607-8. PMID:29214998[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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