Document Detail

Mechanism of Aurora B activation by INCENP and inhibition by hesperadin.
MedLine Citation:
PMID:  15866179     Owner:  NLM     Status:  MEDLINE    
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.
Fabio Sessa; Marina Mapelli; Claudio Ciferri; Cataldo Tarricone; Liliana B Areces; Thomas R Schneider; P Todd Stukenberg; Andrea Musacchio
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular cell     Volume:  18     ISSN:  1097-2765     ISO Abbreviation:  Mol. Cell     Publication Date:  2005 Apr 
Date Detail:
Created Date:  2005-05-03     Completed Date:  2005-06-30     Revised Date:  2011-07-11    
Medline Journal Info:
Nlm Unique ID:  9802571     Medline TA:  Mol Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  379-91     Citation Subset:  IM    
Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
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MeSH Terms
Amino Acid Sequence
Binding Sites
Chromosomal Proteins, Non-Histone / chemistry,  genetics,  metabolism*
Crystallography, X-Ray
Enzyme Activation
Indoles / chemistry,  metabolism*
Models, Molecular
Molecular Sequence Data
Multiprotein Complexes
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary*
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  chemistry*,  genetics,  metabolism*
Sequence Alignment
Sulfonamides / chemistry,  metabolism*
Xenopus laevis
Grant Support
Reg. No./Substance:
0/Chromosomal Proteins, Non-Histone; 0/INCENP protein, human; 0/Indoles; 0/Multiprotein Complexes; 0/Sulfonamides; 0/hesperadin; EC Kinases; EC kinase

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