Journal Article

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

Savitsky, Pavel, Godoi, Paulo H., Mascarello, Alessandra, Massirer, Katlin B., Allerston, Charles K., Wells, Carrow I., Gileadi, Opher, Couñago, Rafael M., Azevedo, Hatylas, Zuercher, William J., Guimarães, Cristiano R. W., de Souza Gama, Fernando H.

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154 / 631/535/1266 / 82/16 / 82/80 / 82/83 / Amino Acid Sequence / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Binding Sites / Cell cycle / Cloning, Molecular / Consortia / Crystallography, X-Ray / DNA probes / Escherichia coli - genetics / Escherichia coli - metabolism / Gene Expression / Genetic Vectors - chemistry / Genetic Vectors - metabolism / Genome, Human / Genomes / Genomics / Humanities and Social Sciences / Humans / Inhibitors / Intracellular Signaling Peptides and Proteins - antagonists & inhibitors / Intracellular Signaling Peptides and Proteins - chemistry / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Kinetics / Ligands / Models, Molecular / multidisciplinary / Protein Binding / Protein Conformation, alpha-Helical / Protein Conformation, beta-Strand / Protein Folding / Protein Interaction Domains and Motifs / Protein kinase / Protein Kinase Inhibitors - chemistry / Protein Kinase Inhibitors - pharmacology / Protein-Serine-Threonine Kinases - antagonists & inhibitors / Protein-Serine-Threonine Kinases - chemistry / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Proteins / Pteridines - chemistry / Pteridines - pharmacology / Recombinant Proteins - chemistry / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Science / Science (multidisciplinary) / Structure-Activity Relationship / Transcription factors / Tumors / Vaccinia / Vaccinia virus - genetics / Vaccinia virus - metabolism