Abstract
The Aurora family is a well conserved and well characterized group of serine-threonine kinases involved in the normal progression of mitosis. The deregulation of Aurora kinases impairs spindle assembly, checkpoint function and cell division. To date, many small molecules that compete with ATP for binding to Aurora kinases have been developed and characterized. Here, the first structure of the Xenopus laevis Aurora B-INCENP complex bound to the clinically relevant small molecule barasertib was determined. The binding properties of this inhibitor to the Aurora B active site are analyzed and reported. An unexpected crystal-packing contact in the Aurora B-INCENP structure coordinated by an ATP analogue is also reported, in which the INCENP C-terminus occupies the substrate-binding region, resembling the protein kinase A inhibitory mechanism.
Highlights
The Aurora proteins are a small family of serine/threonine kinases that are expressed during mitosis and have been suggested to be attractive drug targets (Carpinelli & Moll, 2008; Andrews, 2005)
The chromosome passenger complex (CPC) complex is involved in numerous mitotic functions, and the timing and mechanisms of each of these events are carefully regulated by its localization within mitosis (Carmena et al, 2012)
We report the crystal structure of the Xenopus laevis Aurora B–INCENP complex bound to the active form of barasertib
Summary
The Aurora proteins are a small family of serine/threonine kinases that are expressed during mitosis and have been suggested to be attractive drug targets (Carpinelli & Moll, 2008; Andrews, 2005). Together with INCENP, borealin and survivin, Aurora B kinase forms the chromosome passenger complex (CPC; Carmena et al, 2012). Deregulation of Aurora kinases has drastic intracellular consequences (Meraldi et al, 2004), rendering these kinases attractive drug targets for small-molecule inhibitor development, targeting the active-site binding pocket which binds the ATP substrate (Andrews, 2005). We report the crystal structure of the Xenopus laevis Aurora B–INCENP complex bound to the active form of barasertib. We report the structure of the same complex bound to a nonhydrolyzable nucleotide that induces the formation of a crystal contact mediated by the substrate-recognition region of Aurora B and a neighbouring INCENP molecule
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