7QIE

Crystal Structure of Phosphatidylinositol 5-Phosphate 4-Kinase (PI5P4K2C) bound to an allosteric inhibitor

7QIE の概要

• エントリーDOI: 10.2210/pdb7qie/pdb
• 分子名称: Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma, 5-methyl-2-(2-propan-2-ylphenyl)-~{N}-(pyridin-2-ylmethyl)pyrrolo[3,2-d]pyrimidin-4-amine (3 entities in total)
• 機能のキーワード: allosteric binding, lipid kinase, non-atp-competitive inhibitor, phosphatidylinositol 5-phosphate, transferase
• 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: 169501.48

構造登録者

Howard, T.D.,Ogg, D.T. (登録日: 2021-12-14, 公開日: 2022-05-18, 最終更新日: 2024-01-31)

主引用文献

Boffey, H.K.,Rooney, T.P.C.,Willems, H.M.G.,Edwards, S.,Green, C.,Howard, T.,Ogg, D.,Romero, T.,Scott, D.E.,Winpenny, D.,Duce, J.,Skidmore, J.,Clarke, J.H.,Andrews, S.P.
Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase gamma Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode.
J.Med.Chem., 65:3359-3370, 2022

PubMed Abstract: Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunological disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochemical properties of the selective PI5P4Kγ inhibitor, NIH-12848 (). These improvements enabled the demonstration that this chemotype engages PI5P4Kγ in intact cells and that compounds from this series do not inhibit PI5P4Kα or PI5P4Kβ. Furthermore, the first X-ray structure of PI5P4Kγ bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chemical series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 Å from the ATP pocket.

PubMed: 35148092
DOI: 10.1021/acs.jmedchem.1c01819

実験手法

X-RAY DIFFRACTION (2.39 Å)