title: Co-crystal structures of the protein kinase haspin with bisubstrate inhibitors.
abstract: Haspin is a mitotic protein kinase that is responsible for the phosphorylation of Thr3 of histone H3, thereby creating a recognition motif for docking of the chromosomal passenger complex that is crucial for the progression of cell division. Here, two high-resolution models of haspin with previously reported inhibitors consisting of an ATP analogue and a histone H3(1-7) peptide analogue are presented. The structures of the complexes confirm the bisubstrate character of the inhibitors by revealing the signature binding modes of the moieties targeting the ATP-binding site and the protein substrate-binding site of the kinase. This is the first structural model of a bisubstrate inhibitor targeting haspin. The presented structural data represent a model for the future development of more specific haspin inhibitors.
authors.affiliation: Institute of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Darja
authors.initials: D
authors.lastname: Lavogina
authors.affiliation: Institute of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kestav
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, England.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, England.
authors.forename: Christina
authors.initials: C
authors.lastname: Heroven
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, England.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Institute of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia.
authors.forename: Asko
authors.initials: A
authors.lastname: Uri
mesh_terms: D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C530656:HASPIN protein, human; D017346:Protein Serine-Threonine Kinases
keywords: bisubstrate; haspin; histone; inhibitor; linker; protein kinase