title: Family-wide Structural Analysis of Human Numb-Associated Protein Kinases.
abstract: The highly diverse Numb-associated kinase (NAK) family has been linked to broad cellular functions including receptor-mediated endocytosis, Notch pathway modulation, osteoblast differentiation, and dendrite morphogenesis. Consequently, NAK kinases play a key role in a diverse range of diseases from Parkinson's and prostate cancer to HIV. Due to the plasticity of this kinase family, NAK kinases are often inhibited by approved or investigational drugs and have been associated with side effects, but they are also potential drug targets. The presence of cysteine residues in some NAK family members provides the possibility for selective targeting via covalent inhibition. Here we report the first high-resolution structures of kinases AAK1 and BIKE in complex with two drug candidates. The presented data allow a comprehensive structural characterization of the NAK kinase family and provide the basis for rational design of selective NAK inhibitors.
authors: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute (TDI), University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors: Fiona J
authors: FJ
authors: Sorrell
authors: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute (TDI), University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors: Marta
authors: M
authors: Szklarz
authors: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute (TDI), University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors: Kamal R
authors: KR
authors: Abdul Azeez
authors: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute (TDI), University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors: Jon M
authors: JM
authors: Elkins
authors: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute (TDI), University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK; Institute for Pharmaceutical Chemistry, Buchmann Institute for Life Sciences Campus Riedberg, Goethe-University Frankfurt, 60438 Frankfurt am Main, Germany. Electronic address: knapp@pharmchem.uni-frankfurt.de.
authors: Stefan
authors: S
authors: Knapp
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D003545:Cysteine / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; C451304:AAK1 protein, human; C000612208:BMP2K protein, human; C486325:GAK protein, human; D017346:Protein Serine-Threonine Kinases; C418980:STK16 protein, human; D003545:Cysteine
keywords: AAK1; BIKE; Numb-associated kinase (NAK); activation segment; inhibitor selectivity