2x81

STRUCTURE OF AURORA A IN COMPLEX WITH MLN8054

spinqualitylabelsall models 2x81, resolution 2.91Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2x81 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.91Å Ligands: ZZL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AURKA_HUMAN Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed The Aurora kinases regulate multiple aspects of mitotic progression and their overexpression in diverse tumour types makes them appealing oncology targets. An intensive research effort over the last decade has led to the discovery of chemically distinct families of small molecule Aurora kinase inhibitors, many of which have demonstrated therapeutic potential in model systems. These agents are also important tools to help dissect signalling pathways that are orchestrated by Aurora kinases, and the anti-proliferative target of pan-Aurora inhibitors such as VX-680 has been validated using chemical genetic techniques. In many cases the non-specific nature of Aurora inhibitors towards unrelated kinases is well established, potentially broadening the spectrum of cancers to which these compounds might be applied. However, unambiguously demonstrating the molecular target(s) for clinical kinase inhibitors is an important challenge, and one that is absolutely critical for deciphering the molecular basis of compound specificity, resistance and efficacy. In this paper, we have investigated amino acid requirements for Aurora A sensitivity to the benzazepine-based Aurora inhibitor MLN8054 and the close analog MLN8237, a second-generation compound that is in phase II clinical trials. A crystallographic analysis facilitated the design and biochemical investigation of a panel of resistant Aurora A mutants, a subset of which were then selected as candidate drug-resistance targets for further evaluation. Using inducible human cell lines, we show that cells expressing near-physiological levels of a functional, but partially drug-resistant, Aurora A T217D mutant survive in the presence of MLN8054 or MLN8237, authenticating Aurora A as a critical anti-proliferative target of these compounds. Drug-resistant Aurora A mutants for cellular target validation of the small molecule kinase inhibitors MLN8054 and MLN8237.,Sloane D, Trikic M, Chu ML, Lamers M, Mason C, Mueller I, Savory W, Williams DH, Eyers PA ACS Chem Biol. 2010 Apr 28. PMID:20426425 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine/threonine protein kinase 3D structures

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