title: The high-resolution crystal structure of phosphatidylinositol 4-kinase IIβ and the crystal structure of phosphatidylinositol 4-kinase IIα containing a nucleoside analogue provide a structural basis for isoform-specific inhibitor design.
abstract: Phosphatidylinositol 4-phosphate (PI4P) is the most abundant monophosphoinositide in eukaryotic cells. Humans have four phosphatidylinositol 4-kinases (PI4Ks) that synthesize PI4P, among which are PI4K IIβ and PI4K IIα. In this study, two crystal structures are presented: the structure of human PI4K IIβ and the structure of PI4K IIα containing a nucleoside analogue. The former, a complex with ATP, is the first high-resolution (1.9 Å) structure of a PI4K. These structures reveal new details such as high conformational heterogeneity of the lateral hydrophobic pocket of the C-lobe and together provide a structural basis for isoform-specific inhibitor design.
authors.affiliation: Department of Biochemistry, Institute of Organic Chemistry and Biochemistry, Flemingovo nam. 2, 166 10 Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Klima
authors.affiliation: Department of Biochemistry, Institute of Organic Chemistry and Biochemistry, Flemingovo nam. 2, 166 10 Prague, Czech Republic.
authors.forename: Adriana
authors.initials: A
authors.lastname: Baumlova
authors.affiliation: Department of Biochemistry, Institute of Organic Chemistry and Biochemistry, Flemingovo nam. 2, 166 10 Prague, Czech Republic.
authors.forename: Dominika
authors.initials: D
authors.lastname: Chalupska
authors.affiliation: Department of Biochemistry, Institute of Organic Chemistry and Biochemistry, Flemingovo nam. 2, 166 10 Prague, Czech Republic.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hřebabecký
authors.affiliation: Department of Biochemistry, Institute of Organic Chemistry and Biochemistry, Flemingovo nam. 2, 166 10 Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Dejmek
authors.affiliation: Department of Biochemistry, Institute of Organic Chemistry and Biochemistry, Flemingovo nam. 2, 166 10 Prague, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Nencka
authors.affiliation: Department of Biochemistry, Institute of Organic Chemistry and Biochemistry, Flemingovo nam. 2, 166 10 Prague, Czech Republic.
authors.forename: Evzen
authors.initials: E
authors.lastname: Boura
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D009705:Nucleosides; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D019870:1-Phosphatidylinositol 4-Kinase
keywords: ATP; crystal structure; inhibitor; kinase; phosphatidyl inositol