5EUQ

Crystal structure of an engineered construct of phosphatidylinositol 4 kinase III beta with a potent and selective inhibitor in complex with GDP loaded Rab11

5EUQ の概要

• エントリーDOI: 10.2210/pdb5euq/pdb
• 分子名称: Ras-related protein Rab-11A, Phosphatidylinositol 4-kinase beta, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: lipid kinase, gtpase complex, transferase-signaling protein complex, transferase/signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86500.59

構造登録者

Burke, J.E.,Fowler, M.L. (登録日: 2015-11-19, 公開日: 2016-02-24, 最終更新日: 2023-09-27)

主引用文献

Rutaganira, F.U.,Fowler, M.L.,McPhail, J.A.,Gelman, M.A.,Nguyen, K.,Xiong, A.,Dornan, G.L.,Tavshanjian, B.,Glenn, J.S.,Shokat, K.M.,Burke, J.E.
Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase III beta.
J.Med.Chem., 59:1830-1839, 2016

PubMed Abstract: Type III phosphatidylinositol 4-kinase (PI4KIIIβ) is an essential enzyme in mediating membrane trafficking and is implicated in a variety of pathogenic processes. It is a key host factor mediating replication of RNA viruses. The design of potent and specific inhibitors of this enzyme will be essential to define its cellular roles and may lead to novel antiviral therapeutics. We previously reported the PI4K inhibitor PIK93, and this compound has defined key functions of PI4KIIIβ. However, this compound showed high cross reactivity with class I and III PI3Ks. Using structure-based drug design, we have designed novel potent and selective (>1000-fold over class I and class III PI3Ks) PI4KIIIβ inhibitors. These compounds showed antiviral activity against hepatitis C virus. The co-crystal structure of PI4KIIIβ bound to one of the most potent compounds reveals the molecular basis of specificity. This work will be vital in the design of novel PI4KIIIβ inhibitors, which may play significant roles as antiviral therapeutics.

PubMed: 26885694
DOI: 10.1021/acs.jmedchem.5b01311

実験手法

X-RAY DIFFRACTION (3.2 Å)