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.
Author: | Martin SchröderORCiDGND, Li Tan, Jinhua Wang, Yanke Liang, Nathanael S. GrayORCiDGND, Stefan KnappORCiDGND, 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): | Creative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International |