title: Structure of Aurora B-INCENP in complex with barasertib reveals a potential transinhibitory mechanism.
abstract: The Aurora family is a well conserved and well characterized group of serine-threonine kinases involved in the normal progression of mitosis. The deregulation of Aurora kinases impairs spindle assembly, checkpoint function and cell division. To date, many small molecules that compete with ATP for binding to Aurora kinases have been developed and characterized. Here, the first structure of the Xenopus laevis Aurora B-INCENP complex bound to the clinically relevant small molecule barasertib was determined. The binding properties of this inhibitor to the Aurora B active site are analyzed and reported. An unexpected crystal-packing contact in the Aurora B-INCENP structure coordinated by an ATP analogue is also reported, in which the INCENP C-terminus occupies the substrate-binding region, resembling the protein kinase A inhibitory mechanism.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sessa
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Villa
mesh_terms: D000266:Adenylyl Imidodiphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D064107:Aurora Kinase B / Q000737:chemistry*; D020134:Catalytic Domain; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010755:Organophosphates / Q000737:chemistry*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011799:Quinazolines / Q000737:chemistry*; D040681:Structural Homology, Protein; D029867:Xenopus Proteins / Q000737:chemistry*; D014982:Xenopus laevis
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000970:Antineoplastic Agents; D002868:Chromosomal Proteins, Non-Histone; C506222:INCENP protein, Xenopus; D010755:Organophosphates; D011799:Quinazolines; D029867:Xenopus Proteins; D000266:Adenylyl Imidodiphosphate; D064107:Aurora Kinase B
keywords: Aurora kinases; PKA; barasertib; cancer; small-molecule inhibitors