MULTIPLE-MODES OF LIGAND RECOGNITION - CRYSTAL-STRUCTURES OF CYCLIN-DEPENDENT PROTEIN-KINASE-2 IN COMPLEX WITH ATP AND 2 INHIBITORS, OLOMOUCINE AND ISOPENTENYLADENINE

Cyclin-dependent kinases (CDKs) are conserved regulators of the eukary otic 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 c ell cycle regulation makes them a potential new target for inhibitory molecules with anti-proliferative and/or anti-neoplastic effects. We d escribe the crystal structures of the complexes of CDK2 with a weakly specific CDK inhibitor, N6-(Delta(2)-isopentenyl)adenine, and a strong ly specific inhibitor, olomoucine. Both inhibitors are adenine derivat ives and bind in the adenine binding pocket of CDK2, but in an unexpec ted and different orientation from the adenine of the authentic ligand ATP. The N6-benzyl substituent in olomoucine binds outside the conser ved binding pocket and is most likely responsible for its specificity. The structural information from the CDK2-olomoucine complex will be u seful in directing the search for the next generation inhibitors with improved properties. (C) 1995 Wiley-Liss, Inc.