7N81

Crystal Structure of PI5P4KIIBeta complex with CC260

Summary for 7N81

• Entry DOI: 10.2210/pdb7n81/pdb
• Descriptor: Phosphatidylinositol 5-phosphate 4-kinase type-2 beta, (7R)-8-cyclopentyl-7-(cyclopentylmethyl)-2-[(3,5-dichloro-4-hydroxyphenyl)amino]-5-methyl-7,8-dihydropteridin-6(5H)-one (3 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 90091.97

Authors

Chen, S.,Ha, Y. (deposition date: 2021-06-11, release date: 2021-06-30, Last modification date: 2023-10-18)

Primary citation

Chen, S.,Chandra Tjin, C.,Gao, X.,Xue, Y.,Jiao, H.,Zhang, R.,Wu, M.,He, Z.,Ellman, J.,Ha, Y.
Pharmacological inhibition of PI5P4K alpha / beta disrupts cell energy metabolism and selectively kills p53-null tumor cells.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Most human cancer cells harbor loss-of-function mutations in the p53 tumor suppressor gene. Genetic experiments have shown that phosphatidylinositol 5-phosphate 4-kinase α and β (PI5P4Kα and PI5P4Kβ) are essential for the development of late-onset tumors in mice with germline p53 deletion, but the mechanism underlying this acquired dependence remains unclear. PI5P4K has been previously implicated in metabolic regulation. Here, we show that inhibition of PI5P4Kα/β kinase activity by a potent and selective small-molecule probe disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition in a variety of cell types. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling in terminally differentiated myotubes. Most significantly, the energy stress induced by PI5P4Kαβ inhibition is selectively toxic toward p53-null tumor cells. The chemical probe, and the structural basis for its exquisite specificity, provide a promising platform for further development, which may lead to a novel class of diabetes and cancer drugs.

PubMed: 34001596
DOI: 10.1073/pnas.2002486118

Experimental method

X-RAY DIFFRACTION (2.7 Å)