5V02

A positive allosteric modulator binding pocket in SK2 ion channels is shared by Riluzole and CyPPA

5V02 の概要

• エントリーDOI: 10.2210/pdb5v02/pdb
• 分子名称: Small conductance calcium-activated potassium channel protein 2, Calmodulin-1, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: calcium-activated ion channels, activator, calmodulin, transport protein-metal binding protein complex, transport protein/metal binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Membrane; Multi-pass membrane protein: Q9H2S1; Cytoplasm, cytoskeleton, spindle : P0DP23
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29694.51

構造登録者

Liu, S. (登録日: 2017-02-28, 公開日: 2018-03-07, 最終更新日: 2023-10-04)

主引用文献

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

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: 29576321
DOI: 10.1016/j.str.2018.02.017

実験手法

X-RAY DIFFRACTION (1.78 Å)