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.

Download full text files

Export metadata

Additional Services

Share in Twitter Search Google Scholar
Metadaten
Author:Martin SchröderORCiDGND, Li Tan, Jinhua Wang, Yanke Liang, Nathanael S. GrayORCiDGND, Stefan KnappORCiD, Apirat ChaikuadORCiD
URN:urn:nbn:de:hebis:30:3-727692
DOI:https://doi.org/10.1101/2020.06.11.145995
Parent Title (English):bioRxiv
Document Type:Preprint
Language:English
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
Issue:2020.06.11.145995
Page Number:27
HeBIS-PPN:510602886
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
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International