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

Abstract

PDB reference: MK2-TEI-L03090 complex, 3wi6Mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAP-K2), a serine/threonine kinase from the p38 mitogen-activated protein kinase signalling pathway, plays an important role in the production of TNF-and other cytokines. In a previous report, it was shown that MK2 in complex with the selective inhibitor TEI-I01800 adopts an -helical glycine-rich loop that is induced by the stable nonplanar conformer of TEI-I01800. To understand the mechanism of the structural change, the structure of MK2 bound to TEI-L03090, which lacks the key substituent found in TEI-I01800, was determined. MK2-TEI-L03090 has a -sheet glycine-rich loop in common with other kinases, as predicted. This result suggests that a small compound can induce a drastic conformational change in the target protein structure and can be used to design potent and selective inhibitors.

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

“…The new tricyclic compound 91 (also referred to as TEI-L03090, Table ) showed micromolar inhibitory activity toward both MK2 and CDK2 (4700 and 630 nM, respectively), without appreciable selectivity. It was cocrystallized with MK2 that showed a Gly-rich loop in an β-sheet form (PDB entry 3wi6, 2.99 Å resolution) . The N1 and 8-NH of the inhibitor showed two hydrogen bonds with both the NH and carbonyl groups of Leu141.…”

“…It was cocrystallized with MK2 that showed a Gly-rich loop in an β-sheet form (PDB entry 3wi6, 2.99 Å resolution). 40 The N1 and 8-NH of the inhibitor showed two hydrogen bonds with both the NH and carbonyl groups of Leu141. Moreover, the piperidino basic nitrogen was involved in an additional hydrogen bonds with the backbone carbonyl group of Glu190.…”