Crystal structure of human cyclin-dependent kinase-2 complex with MK2 inhibitor TEI-I01800: insight into the selectivity

Mitogen‐activated protein kinase‐activated protein kinase 2 (MK2 or MAPKAP‐K2) is a Ser/Thr kinase from the p38 mitogen‐activated protein kinase signalling pathway and plays an important role in inflammatory diseases. The crystal structure of the MK2–TEI‐I01800 complex has been reported; its Gly‐rich loop was found to form an α‐helix, not a β‐sheet as has been observed for other Ser/Thr kinases. TEI‐I01800 is 177‐fold selective against MK2 compared with CDK2; in order to understand the inhibitory mechanism of TEI‐I01800, the cyclin‐dependent kinase 2 (CDK2) complex structure with TEI‐I01800 was determined at 2.0 Å resolution. Interestingly, the Gly‐rich loop of CDK2 formed a β‐sheet that was different from that of MK2. In MK2, TEI‐I01800 changed the secondary structure of the Gly‐rich loop from a β‐sheet to an α‐helix by collision between Leu70 and a p‐ethoxyphenyl group at the 7‐position and bound to MK2. However, for CDK2, TEI‐I01800 bound to CDK2 without this structural change and lost the interaction with the substituent at the 7‐position. In summary, the results of this study suggest that the reason for the selectivity of TEI‐I01800 is the favourable conformation of TEI‐I01800 itself, making it suitable for binding to the α‐form MK2.