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

Acta Crystallogr D Biol Crystallogr. 2015 Jul;71(Pt 7):1555-63. doi: 10.1107/S1399004715009505. Epub 2015 Jun 30.

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.

Keywords: ATP; crystal structure; inhibitor; kinase; phosphatidyl inositol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / antagonists & inhibitors
  • 1-Phosphatidylinositol 4-Kinase / chemistry*
  • 1-Phosphatidylinositol 4-Kinase / metabolism
  • Adenosine Triphosphate / metabolism
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Nucleosides / chemistry*
  • Nucleosides / pharmacology
  • Protein Conformation
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology

Substances

  • Nucleosides
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • 1-Phosphatidylinositol 4-Kinase