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Published on: May 24, 2020
Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies
Rafael M Couñago1,2, Charles K Allerston3, Pavel Savitsky3
1Structural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, SP, Brazil. rafael.counago@unicamp.br.
Abstract:
The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes and linked to a variety of tumors. However, understanding the cellular role of VRKs and establishing their potential use as targets for therapeutic intervention has been limited by the lack of tool compounds that can specifically modulate the activity of these kinases in cells. Here we identified BI-D1870, a dihydropteridine inhibitor of RSK kinases, as a promising starting point for the development of chemical probes targeting the active VRKs. We solved co-crystal structures of both VRK1 and VRK2 bound to BI-D1870 and of VRK1 bound to two broad-spectrum inhibitors. These structures revealed that both VRKs can adopt a P-loop folded conformation, which is stabilized by different mechanisms on each protein. Based on these structures, we suggest modifications to the dihydropteridine scaffold that can be explored to produce potent and specific inhibitors towards VRK1 and VRK2.
Insights
Researchers identified BI-D1870 as a starting point for developing chemical probes targeting Vaccinia-related protein kinases (VRKs). Structural analysis revealed insights for creating specific VRK1 and VRK2 inhibitors for therapeutic applications.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- The human genome contains two active Vaccinia-related protein kinases (VRKs), VRK1 and VRK2, involved in cellular processes and cancer.
- Understanding VRK functions and therapeutic potential is hindered by the absence of specific chemical modulators.
Purpose of the Study:
- To identify and develop chemical probes for modulating VRK1 and VRK2 activity.
- To elucidate the structural basis for VRK inhibition and guide the design of targeted therapeutics.
Main Methods:
- Screening of kinase inhibitors to identify potential VRK modulators.
- Co-crystallization of VRK1 and VRK2 with identified inhibitors (BI-D1870 and broad-spectrum inhibitors).
- X-ray crystallography to determine the structures of VRK-inhibitor complexes.
Main Results:
- BI-D1870, an RSK kinase inhibitor, was identified as a promising starting point for VRK probe development.
- Co-crystal structures revealed VRK1 and VRK2 bound to BI-D1870, and VRK1 bound to other inhibitors.
- Both VRK1 and VRK2 adopt a P-loop folded conformation, stabilized differently in each kinase.
Conclusions:
- BI-D1870 serves as a valuable scaffold for developing specific VRK1 and VRK2 inhibitors.
- Structural insights provide a foundation for designing potent and selective dihydropteridine-based VRK inhibitors.
- This work facilitates further investigation into VRK roles and their therapeutic targeting in diseases like cancer.
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