Figure 5

Structural basis for PHA-00781089 selectivity. The 3D structure of CDK2 (PDB 2A4L, wire rendering with grey carbons) was superposed onto the structure of MK2 (hidden) in complex with PHA-00781089 (PDB 2P3G, ball and stick rendering with green carbons). Anderson et al [22] demonstrated that the fluorophenyl of PHA-00781089 provided selectivity against CDK2 as a compound without this substituent was a potent inhibitor of CDK2. Consistent with this observation, the fluorophenyl of PHA-00781089 makes a number of clashes (orange lines) with Phe 82 (stick rendering with grey carbons) of CDK2, whereas Cys 140 (stick with green carbons) of MK2 accommodates the inhibitor. We therefore conclude that S-Filter correctly predicted Cys 140 as a specificity determinant.