title: Analysis of water patterns in protein kinase binding sites.
abstract: Deregulation of protein kinases is associated with numerous diseases, making them important targets for drug discovery. The majority of drugs target the catalytic site of these proteins, but due to the high level of similarity within the ATP binding sites of protein kinases, it is often difficult to achieve the required pharmacological selectivity. In this study, we describe the identification and subsequent analysis of water patterns in the ATP binding sites of 171 protein kinase structures, comprising 19 different kinases from various branches of the kinome, and demonstrate that structurally similar binding sites often have significantly different water patterns. We show that the observed variations in water patterns of different, but structurally similar kinases can be exploited in the structure-based design of potent and selective kinase inhibitors.
authors.affiliation: Section of Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Caterina
authors.initials: C
authors.lastname: Barillari
authors.forename: Anna L
authors.initials: AL
authors.lastname: Duncan
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Westwood
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
authors.forename: Rob L M
authors.initials: RL
authors.lastname: van Montfort
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D016000:Cluster Analysis; D030562:Databases, Protein; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: D014867:Water; D000255:Adenosine Triphosphate; D011494:Protein Kinases