2VGO

Crystal structure of Aurora B kinase in complex with Reversine inhibitor

Summary for 2VGO

• Entry DOI: 10.2210/pdb2vgo/pdb
• Related: 2BFX 2BFY 2VGP
• Descriptor: SERINE/THREONINE-PROTEIN KINASE 12-A, INNER CENTROMERE PROTEIN A, N~6~-cyclohexyl-N~2~-(4-morpholin-4-ylphenyl)-9H-purine-2,6-diamine, ... (4 entities in total)
• Functional Keywords: nucleotide-binding, serine/threonine-protein kinase, atp-binding, transferase, coiled coil, cell division, kinase, cancer, incenp, nucleus, mitosis, aurora b, metal-binding, aminothiazole, phosphorylation, magnesium, cell cycle, centromere, microtubule
• Biological source: XENOPUS LAEVIS (AFRICAN CLAWED FROG); More
• Cellular location: Nucleus: Q6DE08; Chromosome, centromere: O13024
• Total number of polymer chains: 4
• Total formula weight: 78010.22

Authors

D'Alise, A.M.,Amabile, G.,Iovino, M.,Di Giorgio, F.P.,Bartiromo, M.,Sessa, F.,Villa, F.,Musacchio, A.,Cortese, R. (deposition date: 2007-11-15, release date: 2008-10-28, Last modification date: 2024-10-23)

Primary citation

D'Alise, A.M.,Amabile, G.,Iovino, M.,Di Giorgio, F.P.,Bartiromo, M.,Sessa, F.,Villa, F.,Musacchio, A.,Cortese, R.
Reversine, a Novel Aurora Kinases Inhibitor, Inhibits Colony Formation of Human Acute Myeloid Leukemia Cells.
Mol.Cancer Ther., 7:1140-, 2008

PubMed Abstract: The demonstration that the small synthetic molecule reversine [2-(4-morpholinoanilino)-N6-cyclohexyladenine] promotes the dedifferentiation of committed cells into multipotent progenitor-type cells has raised hopes on the exploitation of this small chemical tool for the generation of stem cells. Here, we show that reversine causes a failure in cytokinesis and induces polyploidization. These effects of reversine are due to the inhibition of Aurora A and B, two related kinases that are implicated in several aspects of mitosis and that are frequently amplified and overexpressed in human tumors. Reversine inhibits the phosphorylation of histone H3, a direct downstream target of Aurora kinases. Similarly to the Aurora kinase inhibitor VX-680, which has recently entered phase II clinical trials for cancer treatment, reversine inhibited colony formation of leukemic cells from patients with acute myeloid leukemia but was significantly less toxic than VX-680 on cells from healthy donors. The crystal structure of the reversine-Aurora B kinase complex shows that reversine is a novel class of ATP-competitive Aurora kinase inhibitors. Thus, although our studies raise serious doubts on the application of reversine in regenerative medicine, they support the paradigm that reversine might be a useful agent in cancer chemotherapy.

PubMed: 18483302
DOI: 10.1158/1535-7163.MCT-07-2051

Experimental method

X-RAY DIFFRACTION (1.7 Å)