6ac9
From Proteopedia
Crystal structure of human Vaccinia-related kinase 1 (VRK1) in complex with AMP-PNP
Structural highlights
Disease[VRK1_HUMAN] Pontocerebellar hypoplasia type 1. The disease is caused by mutations affecting the gene represented in this entry. Function[VRK1_HUMAN] Serine/threonine kinase involved in Golgi disassembly during the cell cycle: following phosphorylation by PLK3 during mitosis, required to induce Golgi fragmentation. Acts by mediating phosphorylation of downstream target protein. Phosphorylates 'Thr-18' of p53/TP53 and may thereby prevent the interaction between p53/TP53 and MDM2. Phosphorylates casein and histone H3. Phosphorylates BANF1: disrupts its ability to bind DNA, reduces its binding to LEM domain-containing proteins and causes its relocalization from the nucleus to the cytoplasm. Phosphorylates ATF2 which activates its transcriptional activity.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedVaccinia-related kinase 1 (VRK1), a serine/threonine mitotic kinase, is widely over-expressed in dividing cells and regarded as a cancer drug target primarily due to its function as an early response gene in cell proliferation. However, the mechanism of VRK1 phosphorylation and substrate activation is not well understood. More importantly even the molecular basis of VRK1 interaction with its cofactor, adenosine triphosphate (ATP), is unavailable to-date. As designing specific inhibitors remains to be the major challenge in kinase research, such a molecular understanding will enable us to design ATP-competitive specific inhibitors of VRK1. Here we report the molecular characterization of VRK1 in complex with AMP-PNP, a non-hydrolyzable ATP-analog, using NMR titration followed by the co-crystal structure determined upto 2.07 A resolution. We also carried out the structural comparison of the AMP-PNP bound-form with its apo and inhibitor-bound counterparts, which has enabled us to present our rationale toward designing VRK1-specific inhibitors. Crystal structure of human vaccinia-related kinase 1 in complex with AMP-PNP, a non-hydrolyzable ATP analog.,Ngow YS, Rajan S, Ye H, Yoon HS Protein Sci. 2018 Nov 21. doi: 10.1002/pro.3552. PMID:30461091[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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