8A9I

PI3KC2a core in complex with PITCOIN1

8A9I の概要

• エントリーDOI: 10.2210/pdb8a9i/pdb
• 関連するPDBエントリー: 7Z74 7Z75
• 分子名称: Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha, 2-[4-oxidanylidene-3-(2-phenylethyl)pteridin-2-yl]sulfanyl-~{N}-(1,3-thiazol-2-yl)ethanamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: pi3kc2 alpha, kinase, transferase
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 103130.72

構造登録者

Lo, W.T.,Roske, Y.,Daumke, O.,Haucke, V. (登録日: 2022-06-28, 公開日: 2022-08-31, 最終更新日: 2024-01-31)

主引用文献

Lo, W.T.,Belabed, H.,Kucukdisli, M.,Metag, J.,Roske, Y.,Prokofeva, P.,Ohashi, Y.,Horatscheck, A.,Cirillo, D.,Krauss, M.,Schmied, C.,Neuenschwander, M.,von Kries, J.P.,Medard, G.,Kuster, B.,Perisic, O.,Williams, R.L.,Daumke, O.,Payrastre, B.,Severin, S.,Nazare, M.,Haucke, V.
Development of selective inhibitors of phosphatidylinositol 3-kinase C2 alpha.
Nat.Chem.Biol., 19:18-27, 2023

PubMed Abstract: Phosphatidylinositol 3-kinase type 2α (PI3KC2α) and related class II PI3K isoforms are of increasing biomedical interest because of their crucial roles in endocytic membrane dynamics, cell division and signaling, angiogenesis, and platelet morphology and function. Herein we report the development and characterization of PhosphatidylInositol Three-kinase Class twO INhibitors (PITCOINs), potent and highly selective small-molecule inhibitors of PI3KC2α catalytic activity. PITCOIN compounds exhibit strong selectivity toward PI3KC2α due to their unique mode of interaction with the ATP-binding site of the enzyme. We demonstrate that acute inhibition of PI3KC2α-mediated synthesis of phosphatidylinositol 3-phosphates by PITCOINs impairs endocytic membrane dynamics and membrane remodeling during platelet-dependent thrombus formation. PITCOINs are potent and selective cell-permeable inhibitors of PI3KC2α function with potential biomedical applications ranging from thrombosis to diabetes and cancer.

PubMed: 36109648
DOI: 10.1038/s41589-022-01118-z

実験手法

X-RAY DIFFRACTION (2.87 Å)