Elkins JM et al. (2012), Crystal structure of human aurora B in complex ...

XB-ART-45900

J Med Chem 2012 Sep 13;5517:7841-8. doi: 10.1021/jm3008954.

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Crystal structure of human aurora B in complex with INCENP and VX-680.

Elkins JM , Santaguida S , Musacchio A , Knapp S .

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We present the structure of the human Aurora B kinase domain in complex with the C-terminal Aurora-binding region of human INCENP and the Aurora kinase inhibitor VX-680. The structure unexpectedly reveals a dimeric arrangement of the Aurora B:INCENP complex, which was confirmed to exist in solution by analytical ultracentrifugation. The dimerization involves a domain swap of the activation loop, resulting in a different conformation of the DFG motif as compared to that seen in other kinase complexes with VX-680. The binding of INCENP differs significantly from that seen in the Xenopus laevis Aurora B:INCENP complex currently used as a model for structure-based design for this important oncology target.

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Species referenced: Xenopus laevis
Genes referenced: abl2 aurka aurkb incenp tpx2

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	Figure 1. Chemical structure of compound 1 (VX-680).
	Figure 2. Overview of human Aurora B kinase as compared to X. laevis Aurora B and human Aurora A. (A) Human Aurora B with INCENP colored green and the activation loop colored red. (B) X. laevis Aurora B complex with Hesperadin (PDB ID: 2BFY),8 with INCENP colored green and the activation loop colored red. (C) Human Aurora A complex with 1 (PDB ID: 3E5A),13 with TPX2 colored green and the activation loop colored red.
	Figure 3. Activation loop exchange of Aurora B kinase. (A) The two Aurora B molecules in the dimer are colored in yellow and blue, INCENP is green, and the activation loops are colored red with dashed lines to indicate where the disordered residues would form a connection. Part of the activation loop packs against the αC helix. (B) The electron density at the cross-over point for the domain swap. The two molecules of Aurora B are colored in orange and blue. The dashed lines in red indicate the connections that would be made between Met249 and His250 in the absence of a domain swap. (C) As in panel A but with one Aurora B:INCENP molecule displayed as a surface, showing the binding of the activation loop in the dimeric arrangement. (D) The activation loop residues involved in the binding.
	Figure 4. Sedimentation velocity analysis of AuroraB:INCENP, showing a 2D plot of f/f0 on the Y-axis and s on the X-axis. The smaller and larger peaks correspond to monomeric and dimeric AuroraB:INCENP, respectively. Peak height is indicated by color on a scale from blue to red (strongest).
	Figure 5. Interface between Aurora B kinase and INCENP. (A) Sequence alignment of human and X. laevis INCENP over the C-terminal IN-box region. (B) Comparison of human and X. laevis Aurora B:INCENP binding at site 1 (residues 842–863 of human INCENP) showing the mostly conserved interactions, with two exceptions highlighted. The X. laevis Aurora B and INCENP are colored blue and purple, respectively (X. laevis coordinates were taken from PDB ID 2BFX(8)). (C) Comparison of human and X. laevis Aurora B:INCENP binding at site 2 (residues 868–881 of human INCENP) showing the mostly nonconserved binding conformation, with the exception of the terminal Phe881. (D) Binding detail for site 2 of human Aurora B:INCENP.
	Figure 6. Comparison of binding to 1 by Aurora B, Aurora A, and ABL2. (A) Aurora B:1. (B) Aurora A:1 (PDB ID: 3E5A).13 (C) ABL2:1 (PDB ID: 2XYN).25 (D) Overlay of the DFG motifs of the complexes with 1 of Aurora B (in yellow) and Aurora A (in pink). (E) Overlay of the DFG motifs of the complexes with 1 of Aurora B (in yellow) and ABL2 (in blue).

References [+] :

Adams, Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. 2010, Pubmed