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Researchers determined the crystal structure of activated MAPKAPK2 kinase bound to MK-25, a non-ATP-competitive inhibitor from the furan-2-carboxamide class. The structure reveals that MK-25 binds to an allosteric pocket in the C-lobe of the kinase, formed by rearrangements of specific helices and the activation segment, and overlapping the protein-substrate recognition region. This binding mode differs from conventional ATP-competitive inhibitors and provides structural insights into how this chemotype achieves selectivity.
Why it matters
This discovery identifies a new druggable pocket on MAPKAPK2, a therapeutic target for inflammatory diseases, that could enable development of more selective inhibitors with fewer off-target effects. The structural information provides a foundation for rational design of next-generation non-ATP-competitive drugs that may overcome limitations of current anti-inflammatory therapies.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
MAPK-activated protein kinase 2 (MAPKAPK2, MK2) is a downstream substrate of p38 MAPK that regulates inflammatory signaling and cytokine synthesis, making it an attractive therapeutic target. Although several crystal structures of MAPKAPK2 with ATP-competitive inhibitors have supported drug discovery, structural elucidation of selective non-ATP-competitive inhibitors has remained challenging. MK-25 is a non-ATP-competitive furan-2-carboxamide MAPKAPK2 inhibitor developed at Merck to overcome the selectivity and cellular-efficacy limitations of ATP-competitive chemotypes. Here, we show through isothermal titration calorimetry that MK-25 binds the activated MAPKAPK2, consistent with state-dependent allosteric binding. To determine the binding mode of MK-25, we solved a 2.8 A resolution crystal structure of an activated MAPKAPK2 construct in ternary complex with the ATP-site inhibitor PF-3644022 and a bromo-analogue of MK-25. The ligand occupies a pocket in the C-lobe overlapping the protein-substrate recognition region and formed through rearrangements of D and G helices and the activation segment. These interactions are consistent with the structure-activity relationships reported for the furan-2-carboxamide chemotype and identify a ligandable allosteric pocket that may facilitate future structure-guided design of selective, non-ATP-competitive MAPKAPK2 inhibitors.