Structural characterization of phosphatidylinositol 4-kinase IIIβ in complex with ATP and inhibitor

D. Chalupská, I. Mejdrová, A. Baumlová, R. Nenska, E. Bouřa

Institute of Organic Chemistry and Biochemistry

Phosphatidylinositol 4-kinases (PI4Ks) are crucial enzymes for the maintenance of lipid homeostasis and for the control of intracellular trafficking. Their product – phosphatidylinositol 4-phosphate (PI4P) - is the main lipid marker of the Golgi and the trans-Golgi network and plays a role at the plasma membrane as well. It is also a precursor for higher phosphoinositols. Many, if not all single stranded plus RNA viruses including dangerous human pathogens, replicate in membranous organelles highly enriched in PI4P. Indeed, type III (α and β) PI4Ks were shown to be essential host factors for the replication of single stranded plus RNA viruses. Numerous viruses from Picornaviridae, Coronaviridae and Flaviviridae families depend on the enzymatic activity of PI4K IIIβ. As such, PI4K IIIβ is a potential therapeutic target in the development of broad-spectrum virostatics.

To understand the mechanism of PI4KIIIβ inhibition at the atomic level we have solved crystal structures of PI4K IIIβ in complex with an archetypal inhibitor and with ATP. These structures revealed that the inhibitors occupy the binding site for the adenine ring of the ATP molecule.

The project was supported by the Academy of Sciences Czech Republic (RVO: 61388963). The work of D.C., A.B. and E.B. was supported by MarieCurie FP7-PEOPLE-2012-CIG project number 333916 and by Project InterBioMed LO1302 from Ministry of Education of the Czech Republic. The work was supported by Gilead Sciences, Inc.