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

  • 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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Author:Martin SchröderORCiDGND, Li Tan, Jinhua Wang, Yanke Liang, Nathanael S. GrayORCiDGND, Stefan KnappORCiD, Apirat ChaikuadORCiD
Parent Title (English):bioRxiv
Document Type:Preprint
Date of Publication (online):2020/06/12
Date of first Publication:2020/06/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/08/06
Page Number:27
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International