CRYSTAL-STRUCTURE AND MUTATIONAL ANALYSIS THE HUMAN CDK2 KINASE COMPLEX WITH CELL CYCLE-REGULATORY PROTEIN CKSHS1

The 2.6 Angstrom crystal structure for human cyclin-dependent kinase 2 (CDK2) in complex with CksHs1, a human homolog of essential yeast cel l cycle-regulatory proteins suc1 and Cks1, reveals that CksHs1 binds v ia all four beta strands to the kinase C-terminal robe. This interface is biologically critical, based upon mutational analysis, but far fro m the CDK2 N-terminal lobe, cyclin, and regulatory phosphorylation sit es. CDK2 binds the Cks single domain conformation and interacts with c onserved hydrophobic residues plus His-60 and Glu-63 in their closed b eta-hinge motif conformation. The beta hinge opening to form the Cks b eta-interchanged dimer sterically precludes CDK2 binding, providing a possible mechanism regulating CDK2-Cks interactions. One face of the c omplex exposes the sequence-conserved phosphate-binding region on Cks and the ATP-binding site on CDK2, suggesting that Cks may target CDK2 to other phosphoproteins during the cell cycle.