8F1C

Voltage-gated potassium channel Kv3.1 with novel positive modulator (9M)-9-{5-chloro-6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-4-methylpyridin-3-yl}-2-methyl-7,9-dihydro-8H-purin-8-one (compound 4)

8F1C の概要

• エントリーDOI: 10.2210/pdb8f1c/pdb
• EMDBエントリー: 28793 28795
• 分子名称: Potassium voltage-gated channel subfamily C member 1, ZINC ION, (9M)-9-{5-chloro-6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-4-methylpyridin-3-yl}-2-methyl-7,9-dihydro-8H-purin-8-one, ... (5 entities in total)
• 機能のキーワード: ion channel, positive modulator, voltage gated, voltage gated potassium channel, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 256190.91

構造登録者

Chen, Y.,Ishchenko, A. (登録日: 2022-11-04, 公開日: 2023-10-25, 最終更新日: 2025-05-21)

主引用文献

Chen, Y.T.,Hong, M.R.,Zhang, X.J.,Kostas, J.,Li, Y.,Kraus, R.L.,Santarelli, V.P.,Wang, D.,Gomez-Llorente, Y.,Brooun, A.,Strickland, C.,Soisson, S.M.,Klein, D.J.,Ginnetti, A.T.,Marino, M.J.,Stachel, S.J.,Ishchenko, A.
Identification and structural and biophysical characterization of a positive modulator of human Kv3.1 channels.
Proc.Natl.Acad.Sci.USA, 120:e2220029120-e2220029120, 2023

PubMed Abstract: Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype. Mutations in the Kv3.1 channel have been shown to have implications in various neurological diseases like epilepsy and Alzheimer's disease. Moreover, disruptions in neuronal circuitry involving Kv3.1 have been correlated with negative symptoms of schizophrenia. Here, we report the discovery of a novel positive modulator of Kv3.1, investigate its biophysical properties, and determine the cryo-EM structure of the compound in complex with Kv3.1. Structural analysis reveals the molecular determinants of positive modulation in Kv3.1 channels by this class of compounds and provides additional opportunities for rational drug design for the treatment of associated neurological disorders.

PubMed: 37812700
DOI: 10.1073/pnas.2220029120

実験手法

ELECTRON MICROSCOPY (2.92 Å)