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.

Crystal Structure of Human Aurora B in Complex with INCENP and VX-680 / J. Elkins, S. Santaguida, A. Musacchio, S. Knapp. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 55:17(2012), pp. 7841-7848.

Crystal Structure of Human Aurora B in Complex with INCENP and VX-680

Santaguida S;
2012

Abstract

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.
Small-molecule inhibitor; size-distribution analysis; kinase inhibitors; analytical ultracentrifugation; antitumor-activity; cell-division; A kinase; in-vivo; activation; mechanism
Settore BIO/11 - Biologia Molecolare
JOURNAL OF MEDICINAL CHEMISTRY
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/622992
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