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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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Couñago RM, Allerston CK, Savitsky P, Azevedo H, Godoi PH, Wells CI, Mascarello A, de Souza Gama FH, Massirer KB, Zuercher WJ, Guimarães CRW, Gileadi O
OpenAccess logo Sci Rep 7 7501 (2017)
Related entries: 3op5, 5ukf, 5uvf

Cited: 17 times
EuropePMC logo PMID: 28790404

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.

Articles - 5uu1 mentioned but not cited (1)

  1. Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations. Couñago RM, Allerston CK, Savitsky P, Azevedo H, Godoi PH, Wells CI, Mascarello A, de Souza Gama FH, Massirer KB, Zuercher WJ, Guimarães CRW, Gileadi O. Sci Rep 7 7501 (2017)


Reviews citing this publication (2)

  1. Emerging roles of the αC-β4 loop in protein kinase structure, function, evolution, and disease. Yeung W, Ruan Z, Kannan N. IUBMB Life 72 1189-1202 (2020)
  2. An overview of kinase downregulators and recent advances in discovery approaches. Wang B, Wu H, Hu C, Wang H, Liu J, Wang W, Liu Q. Signal Transduct Target Ther 6 423 (2021)

Articles citing this publication (14)



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