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Sci Rep. 2017 Aug 8;7(1):7501. doi: 10.1038/s41598-017-07755-y.

Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations.

Author information

1
Structural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, SP, Brazil. rafael.counago@unicamp.br.
2
Centro de Biologia Molecular e Engenharia Genética, Universidade Estadual de Campinas, Campinas, SP, Brazil. rafael.counago@unicamp.br.
3
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, UK.
4
Aché Laboratórios Farmacêuticos SA, Guarulhos, SP, Brazil.
5
Structural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, SP, Brazil.
6
Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas, Campinas, Brazil.
7
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
8
Centro de Biologia Molecular e Engenharia Genética, Universidade Estadual de Campinas, Campinas, SP, Brazil.

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.

PMID:
28790404
PMCID:
PMC5548783
DOI:
10.1038/s41598-017-07755-y
[Indexed for MEDLINE]
Free PMC Article

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