3OP5

Human vaccinia-related kinase 1

Summary for 3OP5

• Entry DOI: 10.2210/pdb3op5/pdb
• Descriptor: Serine/threonine-protein kinase VRK1, [4-({4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}amino)phenyl]acetonitrile, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: adenosine triphosphate, amino acid sequence, binding sites, catalytic domain, models, molecular, molecular sequence data, phosphotransferases, protein conformation, protein folding, surface entropy reduction, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 166372.52

Authors

Allerston, C.K.,Uttarkar, S.,Savitsky, P.,Elkins, J.M.,Filippakopoulos, P.,Krojer, T.,Rellos, P.,Fedorov, O.,Eswaran, J.,Brenner, B.,Keates, T.,Das, S.,King, O.,Chalk, R.,Berridge, G.,von Delft, F.,Gileadi, O.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2010-08-31, release date: 2010-09-22, Last modification date: 2023-09-06)

Primary citation

Counago, R.M.,Allerston, C.K.,Savitsky, P.,Azevedo, H.,Godoi, P.H.,Wells, C.I.,Mascarello, A.,de Souza Gama, F.H.,Massirer, K.B.,Zuercher, W.J.,Guimaraes, C.R.W.,Gileadi, O.
Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations.
Sci Rep, 7:7501-7501, 2017

PubMed 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.

PubMed: 28790404
DOI: 10.1038/s41598-017-07755-y

Experimental method

X-RAY DIFFRACTION (2.4 Å)