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 A 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 alpha-helix structure and not a beta-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 alpha-helical Gly-rich loop
and TEI-I01800 regulates the secondary structure of the Gly-rich loop.
