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

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 target...

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Autores principales:	Rafael M. Couñago, Charles K. Allerston, Pavel Savitsky, Hatylas Azevedo, Paulo H. Godoi, Carrow I. Wells, Alessandra Mascarello, Fernando H. de Souza Gama, Katlin B. Massirer, William J. Zuercher, Cristiano R. W. Guimarães, Opher Gileadi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d22a9c457cc045fe83ff71cae34b8e46
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spelling	oai:doaj.org-article:d22a9c457cc045fe83ff71cae34b8e462021-12-02T15:05:57ZStructural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations10.1038/s41598-017-07755-y2045-2322https://doaj.org/article/d22a9c457cc045fe83ff71cae34b8e462017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07755-yhttps://doaj.org/toc/2045-2322Abstract 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.Rafael M. CouñagoCharles K. AllerstonPavel SavitskyHatylas AzevedoPaulo H. GodoiCarrow I. WellsAlessandra MascarelloFernando H. de Souza GamaKatlin B. MassirerWilliam J. ZuercherCristiano R. W. GuimarãesOpher GileadiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rafael M. Couñago Charles K. Allerston Pavel Savitsky Hatylas Azevedo Paulo H. Godoi Carrow I. Wells Alessandra Mascarello Fernando H. de Souza Gama Katlin B. Massirer William J. Zuercher Cristiano R. W. Guimarães Opher Gileadi Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations
description	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.
format	article
author	Rafael M. Couñago Charles K. Allerston Pavel Savitsky Hatylas Azevedo Paulo H. Godoi Carrow I. Wells Alessandra Mascarello Fernando H. de Souza Gama Katlin B. Massirer William J. Zuercher Cristiano R. W. Guimarães Opher Gileadi
author_facet	Rafael M. Couñago Charles K. Allerston Pavel Savitsky Hatylas Azevedo Paulo H. Godoi Carrow I. Wells Alessandra Mascarello Fernando H. de Souza Gama Katlin B. Massirer William J. Zuercher Cristiano R. W. Guimarães Opher Gileadi
author_sort	Rafael M. Couñago
title	Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations
title_short	Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations
title_full	Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations
title_fullStr	Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations
title_full_unstemmed	Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations
title_sort	structural characterization of human vaccinia-related kinases (vrk) bound to small-molecule inhibitors identifies different p-loop conformations
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d22a9c457cc045fe83ff71cae34b8e46
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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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