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

DOI: 10.1038/s41598-017-07755-y

Authors: Rafael M. Counago (Structural Genomics Consortium, Universidade Estadual de Campinas) , Charles K. Allerston (Structural Genomics Consortium and Target Discovery Institute, University of Oxford) , Pavel Savitsky (Structural Genomics Consortium and Target Discovery Institute, University of Oxford) , Hatylas Azevedo (Aché Laboratórios Farmacêuticos SA) , Paulo H. Godoi (Structural Genomics Consortium, Universidade Estadual de Campinas; Institute of Biology, State University of Campinas) , Carrow I. Wells (Structural Genomics Consortium, University of North Carolina at Chapel Hill) , Alessandra Mascarello (Aché Laboratórios Farmacêuticos SA) , Fernando H. De Souza Gama (Aché Laboratórios Farmacêuticos SA) , Katlin B. Massirer (Structural Genomics Consortium, Universidade Estadual de Campinas) , William J. Zuercher (Structural Genomics Consortium, University of North Carolina at Chapel Hill) , Cristiano R. W. Guimarães (Aché Laboratórios Farmacêuticos SA) , Opher Gileadi (Structural Genomics Consortium, Universidade Estadual de Campinas; University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Scientific Reports , VOL 7

State: Published (Approved)
Published: December 2017
Diamond Proposal Number(s): 12988 , 10619

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.

Journal Keywords: Drug discovery; X-ray crystallography

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Other Facilities: Laboratório Nacional de Luz Síncrotron (LNLS)

Added On: 12/04/2018 10:09

Documents:
s41598-017-07755-y.pdf

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)