Crystal structure of human aurora B in complex with INCENP and VX-680.
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.
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom. jon.elkins@sgc.ox.ac.uk
Jonathan M
JM
Elkins
Stefano
S
Santaguida
Andrea
A
Musacchio
Stefan
S
Knapp
D000595:Amino Acid Sequence; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010879:Piperazines / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D064107:Aurora Kinase B; D064127:Aurora Kinases; D002868:Chromosomal Proteins, Non-Histone; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C083767:INCENP protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576921:AURKB protein, human