Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine

Proteins. 1995 Aug;22(4):378-91. doi: 10.1002/prot.340220408.


Cyclin-dependent kinases (CDKs) are conserved regulators of the eukaryotic cell cycle with different isoforms controlling specific phases of the cell cycle. Mitogenic or growth inhibitory signals are mediated, respectively, by activation or inhibition of CDKs which phosphorylate proteins associated with the cell cycle. The central role of CDKs in cell cycle regulation makes them a potential new target for inhibitory molecules with anti-proliferative and/or anti-neoplastic effects. We describe the crystal structures of the complexes of CDK2 with a weakly specific CDK inhibitor, N6-(delta 2-isopentenyl)adenine, and a strongly specific inhibitor, olomoucine. Both inhibitors are adenine derivatives and bind in the adenine binding pocket of CDK2, but in an unexpected and different orientation from the adenine of the authentic ligand ATP. The N6-benzyl substituent in olomoucine binds outside the conserved binding pocket and is most likely responsible for its specificity. The structural information from the CDK2-olomoucine complex will be useful in directing the search for the next generation inhibitors with improved properties.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemistry
  • Adenosine Triphosphate / chemistry*
  • Amino Acid Sequence
  • CDC2-CDC28 Kinases*
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / chemistry*
  • Enzyme Inhibitors / chemistry*
  • Humans
  • Isopentenyladenosine
  • Kinetin
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Protein Kinases / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry*
  • Purines / chemistry*
  • Surface Properties


  • Enzyme Inhibitors
  • Ligands
  • Purines
  • N(6)-(delta(2)-isopentenyl)adenine
  • olomoucine
  • Isopentenyladenosine
  • Adenosine Triphosphate
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Adenine
  • Kinetin