title: Mechanism of Aurora B activation by INCENP and inhibition by hesperadin.
abstract: Aurora family serine/threonine kinases control mitotic progression, and their deregulation is implicated in tumorigenesis. Aurora A and Aurora B, the best-characterized members of mammalian Aurora kinases, are approximately 60% identical but bind to unrelated activating subunits. The structure of the complex of Aurora A with the TPX2 activator has been reported previously. Here, we report the crystal structure of Aurora B in complex with the IN-box segment of the inner centromere protein (INCENP) activator and with the small molecule inhibitor Hesperadin. The Aurora B:INCENP complex is remarkably different from the Aurora A:TPX2 complex. INCENP forms a crown around the small lobe of Aurora B and induces the active conformation of the T loop allosterically. The structure represents an intermediate state of activation of Aurora B in which the Aurora B C-terminal segment stabilizes an open conformation of the catalytic cleft, and a critical ion pair in the kinase active site is impaired. Phosphorylation of two serines in the carboxyl terminus of INCENP generates the fully active kinase.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sessa
authors.forename: Marina
authors.initials: M
authors.lastname: Mapelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Ciferri
authors.forename: Cataldo
authors.initials: C
authors.lastname: Tarricone
authors.forename: Liliana B
authors.initials: LB
authors.lastname: Areces
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Schneider
authors.forename: P Todd
authors.initials: PT
authors.lastname: Stukenberg
authors.forename: Andrea
authors.initials: A
authors.lastname: Musacchio
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001665:Binding Sites; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C083767:INCENP protein, human; D007211:Indoles; D046912:Multiprotein Complexes; D013449:Sulfonamides; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C474723:hesperadin