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

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Counago, Rafael M. ; Allerston, Charles K. ; Savitsky, Pavel ; Azevedo, Hatylas ; Godoi, Paulo H. ; Wells, Carrow I. ; Mascarello, Alessandra ; de Souza Gama, Fernando H. ; Massirer, Katlin B. ; Zuercher, William J. ; Guimaraes, Cristiano R. W. ; Gileadi, Opher
Número total de Autores: 12
Tipo de documento: Artigo Científico
Fonte: SCIENTIFIC REPORTS; v. 7, AUG 8 2017.
Citações Web of Science: 3

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. (AU)

Processo FAPESP: 13/50724-5 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto
Beneficiário:Paulo Arruda
Linha de fomento: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE