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bioRxiv · 10.1101/2020.06.11.145995

Catalytic domain plasticity of MKK7 reveals structural mechanisms of allosteric activation and new targeting opportunities

Schroeder, M.·Tan, L.·Wang, J.·Liang, Y.·Gray, N. S.·Knapp, S.·Chaikuad, A.
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Abstract

MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that impact its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small molecule screening campaign yielded multiple scaffolds, including type-II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.

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Schroeder, M., Tan, L., Wang, J., Liang, Y., Gray, N. S., Knapp, S., Chaikuad, A.. 2020-06-12. Catalytic domain plasticity of MKK7 reveals structural mechanisms of allosteric activation and new targeting opportunities. https://doi.org/10.1101/2020.06.11.145995

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