Structure of a human inositol 1,4,5-trisphosphate 3-kinase: substrate binding reveals why it is not a phosphoinositide 3-kinase

Mol Cell. 2004 Sep 10;15(5):689-701. doi: 10.1016/j.molcel.2004.08.004.


Mammalian cells produce a variety of inositol phosphates (InsPs), including Ins(1,4,5)P3 that serves both as a second messenger and as a substrate for inositol polyphosphate kinases (IPKs), which further phosphorylate it. We report the structure of an IPK, the human Ins(1,4,5)P3 3-kinase-A, both free and in complexes with substrates and products. This enzyme catalyzes transfer of a phosphate from ATP to the 3-OH of Ins(1,4,5)P3, and its X-ray crystal structure provides a template for understanding a broad family of InsP kinases. The catalytic domain consists of three lobes. The N and C lobes bind ATP and resemble protein and lipid kinases, despite insignificant sequence similarity. The third lobe binds inositol phosphate and is a unique four-helix insertion in the C lobe. This lobe embraces all of the phosphates of Ins(1,4,5)P3 in a positively charged pocket, explaining the enzyme's substrate specificity and its inability to phosphorylate PtdIns(4,5)P2, the membrane-resident analog of Ins(1,4,5)P3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Amino Acid Motifs / physiology
  • Amino Acid Sequence / physiology
  • Animals
  • Binding Sites / physiology
  • Catalytic Domain / physiology
  • Class Ib Phosphatidylinositol 3-Kinase
  • Crystallography, X-Ray
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism*
  • Isoenzymes / chemistry
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositols / chemistry*
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Binding / physiology*
  • Protein Structure, Tertiary / physiology
  • Sequence Homology, Amino Acid
  • Substrate Specificity


  • Isoenzymes
  • Phosphatidylinositols
  • Inositol 1,4,5-Trisphosphate
  • Adenosine Triphosphate
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Inositol 1,4,5-trisphosphate 3-kinase
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human

Associated data

  • PDB/1W2C
  • PDB/1W2D
  • PDB/1W2F