7QIE

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

Summary for 7QIE

• Entry DOI: 10.2210/pdb7qie/pdb
• Descriptor: 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)
• Functional Keywords: allosteric binding, lipid kinase, non-atp-competitive inhibitor, phosphatidylinositol 5-phosphate, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 169501.48

Authors

Howard, T.D.,Ogg, D.T. (deposition date: 2021-12-14, release date: 2022-05-18, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.39 Å)