TUMOR-SUPPRESSOR P16(INK4A) - DETERMINATION OF SOLUTION STRUCTURE ANDANALYSES OF ITS INTERACTION WITH CYCLIN-DEPENDENT KINASE-4

The solution structure of the tumor suppressor p16(INK4A) has been det ermined by NMR, and important recognition regions of both cdk4 and p16 (INK4A) have been identified. The tertiary structure of p16(INK4A) con tains four helix-turn-helix motifs linked by three loops. Twelve tumor igenic mutants of p16(INK4A) have been constructed and analyzed for th eir structure and activity, and new mutants have been designed rationa lly. A fragment of 58 residues at the N terminus of cdk4 important for p16(INK4A) binding has been identified. The importance of this region was further verified by mutational analysis of cdk4. These results an d docking experiments have been used to assess possible modes of bindi ng between p16(INK4A) and cdk4.