5V02
A positive allosteric modulator binding pocket in SK2 ion channels is shared by Riluzole and CyPPA
Summary for 5V02
| Entry DOI | 10.2210/pdb5v02/pdb |
| Descriptor | Small conductance calcium-activated potassium channel protein 2, Calmodulin-1, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | calcium-activated ion channels, activator, calmodulin, transport protein-metal binding protein complex, transport protein/metal binding protein |
| 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 | 29694.51 |
| Authors | |
| Primary citation | Cho, L.T.,Alexandrou, A.J.,Torella, R.,Knafels, J.,Hobbs, J.,Taylor, T.,Loucif, A.,Konopacka, A.,Bell, S.,Stevens, E.B.,Pandit, J.,Horst, R.,Withka, J.M.,Pryde, D.C.,Liu, S.,Young, G.T. An Intracellular Allosteric Modulator Binding Pocket in SK2 Ion Channels Is Shared by Multiple Chemotypes. Structure, 26:533-544.e3, 2018 Cited by PubMed Abstract: Small conductance potassium (SK) ion channels define neuronal firing rates by conducting the after-hyperpolarization current. They are key targets in developing therapies where neuronal firing rates are dysfunctional, such as in epilepsy, Parkinson's, and amyotrophic lateral sclerosis (ALS). Here, we characterize a binding pocket situated at the intracellular interface of SK2 and calmodulin, which we show to be shared by multiple small-molecule chemotypes. Crystallization of this complex revealed that riluzole (approved for ALS) and an analog of the anti-ataxic agent (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-yl]-amine (CyPPA) bind to and allosterically modulate via this site. Solution-state nuclear magnetic resonance demonstrates that riluzole, NS309, and CyPPA analogs bind at this bipartite pocket. We demonstrate, by patch-clamp electrophysiology, that both classes of ligand interact with overlapping but distinct residues within this pocket. These data define a clinically important site, laying the foundations for further studies of the mechanism of action of riluzole and related molecules. PubMed: 29576321DOI: 10.1016/j.str.2018.02.017 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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