TY  - INPR
A1  - Schröder, Martin
A1  - Tan, Li
A1  - Wang, Jinhua
A1  - Liang, Yanke
A1  - Gray, Nathanael S.
A1  - Knapp, Stefan
A1  - Chaikuad, Apirat
T1  - Catalytic domain plasticity of MKK7 reveals structural mechanisms of allosteric activation and new targeting opportunities
T2  - bioRxiv
N2  - 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.
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/72769
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-727692
IS  - 2020.06.11.145995
ER  -