Figure 2. Activation of CDKs and EGFRs occurs by a similar mechanism.

Panel A. Crystal structures of inactive CDK2⁷⁰ (PDB accession code: 1HCK) and cyclin-A in complex with CDK2⁷¹ (PDB accession code: 1FIN). Panel B. Crystal structures of inactive EGFR tyrosine kinase domain³⁵ (PDB accession code: 1XKK) and active state EGFR-TK³⁶ (PDB accession code: 2GS6). There is a striking similarity between the inactive states of EGFR-TK and CDK2. Activation of these kinases is achieved by a protein-protein interaction that forces a structural rearrangement of the kinase towards the active state. In this figure kinase activation loops are colored orange and the C-helix is colored red. The catalytic glutamic acid is shown as space-filling spheres. The important conformational movements of the C-helix and the activation loop are indicated, but other conformational movements that occur between the active and inactive states are not shown³⁸. The location of the catalytic cleft is indicated. It is important to note that this activating mechanism for wild-type EGFR is different from the disease-associated EGFR mutations.