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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.

Original publication

DOI

10.1016/j.str.2015.12.015

Type

Journal article

Journal

Structure

Publication Date

01/03/2016

Volume

24

Pages

401 - 411

Keywords

AAK1, BIKE, Numb-associated kinase (NAK), activation segment, inhibitor selectivity, Amino Acid Sequence, Binding Sites, Conserved Sequence, Cysteine, Humans, Intracellular Signaling Peptides and Proteins, Models, Molecular, Protein Binding, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Transcription Factors