Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Acta Crystallogr F Struct Biol Commun
2014 Mar 01;70Pt 3:294-8. doi: 10.1107/S2053230X14002118.
Show Gene links
Show Anatomy links
Structure of Aurora B-INCENP in complex with barasertib reveals a potential transinhibitory mechanism.
Sessa F
,
Villa F
.
???displayArticle.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.
Figure 1. Binding of barasertib to the ATP-binding pocket of Aurora B. (a) Chemical structure of barasertib prodrug (red) and the active form (green). (b) The three-dimensional structure of Aurora B in cartoon representation, illustrating the N-terminal small lobe (grey), the C-terminal helical large lobe (white), the short C-terminal extension (green), the αC helix (blue) and the activation loop (red). INCENP (orange) crowns the small lobe of Aurora B, stabilizing an active conformation of the kinase. The active form of barasertib (sticks) and its unbiased F
o − F
c OMIT electron-density map (grey mesh) occupy the ATP-binding pocket at the interface between the small and large lobes. (c) Stick representation of the interaction between the active form of barasertib (green) and selected residues of Aurora B. (d) Structure superimposition of the Aurora B–INCENP–barasertib active form complex (grey) with the Aurora A–TPX-2 complex (cyan; PDB entry 1ol5; Bayliss et al., 2003 ▶). O, N and S atoms are shown in red, blue and yellow, respectively. Hydrogen bonds are shown as dashed lines and bond lengths are indicated in Å.
Figure 2. The INCENP C-terminal extension occupies the Aurora B substrate-recognition surface. (a) The arrangement of Aurora B–INCENP molecules in the asymmetric unit is shown in cartoon and ribbon format in grey (Aurora B) and orange (INCENP). The C-terminal portion of INCENP packs against the Aurora B large C-lobe. (b) Details of the INCENP IN-box (orange) molecular interactions with the Aurora B kinase domain (grey). Calculated electron-density maps for the AMP-PNP and for the INCENP segment are drawn in green and brown, respectively. O, N and S atoms are shown in red, blue and yellow, respectively. (c) Multiple sequence alignment of the INCENP C-terminal region from different species. The alignment is colour-coded based on conservation. A solid red bar indicates the INCENP stretch occupying the Aurora B substrate-recognition surface. Numbering is according to the X. laevis sequence. (d, e) Surface representations of Aurora B with INCENP (d) and of protein kinase A with PKI (PDB entry 1atp; Zheng et al., 1993 ▶) (e). Surfaces are coloured according to the electrostatic potential distribution of the kinases, ramped from blue (positive) to red (negative). (f) Schematic representation of an Aurora B potential transinhibitory model proceeding through an intermolecular mechanism, which may be enhanced by a high local protein concentration. This transinhibition mechanism may be relieved by a pTSS–pThr248 repulsion and lead to full activity of Aurora B. A Ser/Thr phosphatase can then revert the full Aurora B activity to a transinhibited state.
Alexander,
Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling.
2011, Pubmed,
Xenbase
Alexander,
Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling.
2011,
Pubmed
,
Xenbase
Andersen,
Discovery of selective aminothiazole aurora kinase inhibitors.
2008,
Pubmed
,
Xenbase
Andrews,
Aurora kinases: shining lights on the therapeutic horizon?
2005,
Pubmed
Ashby,
Characterization of the interaction of a protein inhibitor with adenosine 3',5'-monophosphate-dependent protein kinases. II. Mechanism of action with the holoenzyme.
1973,
Pubmed
Bayliss,
Structural basis of Aurora-A activation by TPX2 at the mitotic spindle.
2003,
Pubmed
,
Xenbase
Bishop,
Phosphorylation of the carboxyl terminus of inner centromere protein (INCENP) by the Aurora B Kinase stimulates Aurora B kinase activity.
2002,
Pubmed
Bolton,
Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity is stimulated by survivin binding and phosphorylation.
2002,
Pubmed
,
Xenbase
Carmena,
The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis.
2012,
Pubmed
Carmena,
The cellular geography of aurora kinases.
2003,
Pubmed
,
Xenbase
Carpinelli,
Aurora kinases and their inhibitors: more than one target and one drug.
2008,
Pubmed
D'Alise,
Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells.
2008,
Pubmed
DeLuca,
Temporal changes in Hec1 phosphorylation control kinetochore-microtubule attachment stability during mitosis.
2011,
Pubmed
Dodson,
Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design.
2010,
Pubmed
Emsley,
Features and development of Coot.
2010,
Pubmed
Foley,
Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase.
2011,
Pubmed
Girdler,
Molecular basis of drug resistance in aurora kinases.
2008,
Pubmed
Honda,
Exploring the functional interactions between Aurora B, INCENP, and survivin in mitosis.
2003,
Pubmed
Kabsch,
XDS.
2010,
Pubmed
Kelly,
Chromosomal enrichment and activation of the aurora B pathway are coupled to spatially regulate spindle assembly.
2007,
Pubmed
,
Xenbase
Knighton,
Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase.
1991,
Pubmed
Meraldi,
Aurora kinases link chromosome segregation and cell division to cancer susceptibility.
2004,
Pubmed
Mortlock,
Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase.
2007,
Pubmed
Murshudov,
REFMAC5 for the refinement of macromolecular crystal structures.
2011,
Pubmed
Sessa,
Mechanism of Aurora B activation by INCENP and inhibition by hesperadin.
2005,
Pubmed
,
Xenbase
Walsh,
Krebs EG: Purification and characterization of a protein inhibitor of adenosine 3',5'-monophosphate-dependent protein kinases.
1971,
Pubmed
Winter,
Decision making in xia2.
2013,
Pubmed
Yang,
AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo.
2007,
Pubmed
Zheng,
2.2 A refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor.
1993,
Pubmed
