Structural analysis of an MK2–inhibitor complex: insight into the regulation of the secondary structure of the Gly-rich loop by TEI-I01800

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK2) 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 complex of human MK2 (residues 41–364) with the potent MK2 inhibitor TEI-I01800 (pK_i = 6.9) was determined at 2.9 Å resolution. The MK2 structure in the MK2–TEI-I01800 complex is composed of two domains, as observed for other Ser/Thr kinases; however, the Gly-rich loop in the N-terminal domain forms an α-helix structure and not a β-sheet. TEI-I01800 binds to the ATP-binding site as well as near the substrate-binding site of MK2. Both TEI-­I01800 molecules have a nonplanar conformation that differs from those of other MK2 inhibitors deposited in the Protein Data Bank. The MK2–TEI-I01800 complex structure is the first active MK2 with an α-helical Gly-rich loop and TEI-­I01800 regulates the secondary structure of the Gly-rich loop.