5WC5

Structural insights into the potency of SK/IK channel positive modulators

Summary for 5WC5

• Entry DOI: 10.2210/pdb5wc5/pdb
• Descriptor: Small conductance calcium-activated potassium channel protein 2, Calmodulin-1, SULFATE ION, ... (7 entities in total)
• Functional Keywords: calcium binding protein, metal transport
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane; Multi-pass membrane protein: Q9H2S1; Cytoplasm, cytoskeleton, spindle : P0DP23
• Total number of polymer chains: 2
• Total formula weight: 28589.09

Authors

Nam, Y.W.,Zhang, M. (deposition date: 2017-06-29, release date: 2017-12-20, Last modification date: 2024-03-13)

Primary citation

Nam, Y.W.,Orfali, R.,Liu, T.,Yu, K.,Cui, M.,Wulff, H.,Zhang, M.
Structural insights into the potency of SK channel positive modulators.
Sci Rep, 7:17178-17178, 2017

PubMed Abstract: Small-conductance Ca-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.

PubMed: 29214998
DOI: 10.1038/s41598-017-16607-8

Experimental method

X-RAY DIFFRACTION (2.3 Å)