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

Abstract

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 -helix, not a -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 -sheet that was different from that of MK2. In MK2, TEI-I01800 changed the secondary structure of the Gly-rich loop from a -sheet to an -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 -form MK2.

Structure of the β-form of human MK2 in complex with the non-selective kinase inhibitor TEI-L03090

“…These long hydrogen bonds could be the reason why TEI-L03090 shows weak inhibition. Furthermore, the interactions between Cys140 and TEI-I01800 are important for MK2 activity, as described in our previous study (Fujino et al, 2010(Fujino et al, , 2013Kosugi et al, 2012). TEI-L03090 lacked van der Waals contacts with Cys140 because TEI-L03090 lacks a substituent at the 8-position corresponding to the p-ethyoxyphenyl group at the 7-position of TEI-I01800.…”

“…TEI-I01800 is highly potent and selective against significant kinases and has a 177-fold selectivity for MK2 over CDK2 (its IC 50 values for MK2 and CDK2 are 0.13 and 23 mM, respectively). Furthermore, we have previously reported crystal structures of MK2 and CDK2 in complex with TEI-I01800 (Fujino et al, 2010(Fujino et al, , 2013Kosugi et al, 2012), which revealed that MK2-TEI-I01800 forms an uncommon -helical glycine-rich loop ( -form) which is induced by the stable conformer of TEI-I01800. On the other hand, CDK2-TEI-I01800 adopted the -form commonly observed in CDK2 complexes with a small inhibitor.…”

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

“…This unprofitable interaction pattern may be responsible for the lower affinity of 87 toward CDK2 in comparison to MK2 and consequently for its 177-fold kinase selectivity. 41 …”

“…In the attempt to rationalize the kinase selectivity profile of 87 , analysis of its complex with CDK2 showed a strained conformation of the inhibitor that led to the lack of interactions between its substituent at the position 7 and the ATP binding site of CDK2, that assumed a β-sheet form. This unprofitable interaction pattern may be responsible for the lower affinity of 87 toward CDK2 in comparison to MK2 and consequently for its 177-fold kinase selectivity …”

“…This unprofitable interaction pattern may be responsible for the lower affinity of 87 toward CDK2 in comparison to MK2 and consequently for its 177-fold kinase selectivity. 31 Another study demonstrated that, similarly to the complex between MK2 and 87, 28 2,4-diaminopyrimidine 80 induced the Gly-rich loop to assume an α-helical conformation (PDB entry 3ka0), 32 even if the Lys93-Glu104 salt bridge was maintained. On the contrary, the 2,4-diaminopyrimidine analogue 78 was cocrystallized with MK2 in the β-form (PDB entry 3kc3).…”