RT Journal Article
SR Electronic
T1 Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 112763
DO 10.1101/112763
A1 Rafael M. Couñago
A1 Charles K. Allerston
A1 Pavel Savitsky
A1 Hatylas Azevedo
A1 Paulo H. Godoi
A1 Carrow I. Wells
A1 Alessandra Mascarello
A1 Fernando H. de Souza Gama
A1 Katlin B. Massirer
A1 William J. Zuercher
A1 Cristiano R.W. Guimarães
A1 Opher Gileadi
YR 2017
UL http://biorxiv.org/content/early/2017/03/02/112763.abstract
AB 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.