6CQ8

K2P2.1(TREK-1):ML335 complex

「5VKN」から置き換えられました

6CQ8 の概要

• エントリーDOI: 10.2210/pdb6cq8/pdb
• 関連するPDBエントリー: 6CQ6
• 分子名称: Potassium channel subfamily K member 2, POTASSIUM ION, HEXADECANE, ... (6 entities in total)
• 機能のキーワード: trek-1 ion channel k2p, transport protein
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72728.52

構造登録者

Lolicato, M.,Minor, D.L. (登録日: 2018-03-14, 公開日: 2018-03-28, 最終更新日: 2024-10-23)

主引用文献

Lolicato, M.,Arrigoni, C.,Mori, T.,Sekioka, Y.,Bryant, C.,Clark, K.A.,Minor, D.L.
K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site.
Nature, 547:364-368, 2017

PubMed Abstract: Polymodal thermo- and mechanosensitive two-pore domain potassium (K) channels of the TREK subfamily generate 'leak' currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit. In contrast to other potassium channels, K channels use a selectivity filter 'C-type' gate as the principal gating site. Despite recent advances, poor pharmacological profiles of K channels limit mechanistic and biological studies. Here we describe a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges that restrict interdomain interface movement behind the selectivity filter. Structures of K2.1 (also known as TREK-1) alone and with two selective K2.1 (TREK-1) and K10.1 (TREK-2) activators-an N-aryl-sulfonamide, ML335, and a thiophene-carboxamide, ML402-define a cryptic binding pocket unlike other ion channel small-molecule binding sites and, together with functional studies, identify a cation-π interaction that controls selectivity. Together, our data reveal a druggable K site that stabilizes the C-type gate 'leak mode' and provide direct evidence for K selectivity filter gating.

PubMed: 28693035
DOI: 10.1038/nature22988

実験手法

X-RAY DIFFRACTION (3 Å)