Alternative binding modes of an inhibitor to two different kinases

摘要: Protein kinases are targets for therapeutic agents designed to intervene in signaling processes the diseased state. Most kinase inhibitors directed towards conserved ATP binding site. Because essential features of this site all eukaryotic protein kinases, it is generally assumed that same compound will bind a similar manner different kinases. The inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) selective CK2 (IC50 1.6 micro m) (Sarno et al. (2001) FEBS Letts.496, 44-48). Three other [cyclin-dependent 2 (CDK2), phosphorylase and glycogen synthase 3beta] exhibit approximately 10-fold weaker affinity TBB than CK2. We report crystal structure complex with phospho-CDK2-cyclin A at 2.2 resolution compare interactions those observed bound binds both In CDK2, each four bromine atoms makes polar contacts either main chain oxygens hinge region or water molecules, addition several van der Waals contacts. mode CDK2 from displaced more between N- C-terminal lobes rotated relative pocket wider resulting fewer but does not contact hinge. structures show that, despite conservation pocket, able exploit recognition so can ways two