5UVF

Crystal Structure of the Human vaccinia-related kinase bound to BI-D1870

「5UGE」から置き換えられました

5UVF の概要

• エントリーDOI: 10.2210/pdb5uvf/pdb
• 分子名称: Serine/threonine-protein kinase VRK1, (7S)-2-[(3,5-difluoro-4-hydroxyphenyl)amino]-5,7-dimethyl-8-(3-methylbutyl)-7,8-dihydropteridin-6(5H)-one, PHOSPHATE ION, ... (6 entities in total)
• 機能のキーワード: transferase, protein kinase domain, structural genomics, structural genomics consortium, sgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 167209.44

構造登録者

Counago, R.M.,Bountra, C.,Arruda, P.,Edwards, A.M.,Gileadi, O.,Structural Genomics Consortium (SGC) (登録日: 2017-02-20, 公開日: 2017-03-22, 最終更新日: 2023-10-04)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)