1. Crystal structure of microtubule affinity-regulating kinase 4 catalytic domain in complex with a pyrazolopyrimidine inhibitor.
- Author
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Sack JS, Gao M, Kiefer SE, Myers JE Jr, Newitt JA, Wu S, and Yan C
- Subjects
- Amino Acid Sequence, Humans, Molecular Sequence Data, Protein Conformation, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors metabolism, Crystallization methods, Crystallography, X-Ray methods, Protein Serine-Threonine Kinases chemistry, Protein Serine-Threonine Kinases metabolism, Pyrazoles chemistry, Pyrazoles metabolism, Pyrimidines chemistry, Pyrimidines metabolism
- Abstract
Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase involved in the phosphorylation of MAP proteins that regulate microtubule dynamics. Abnormal activity of MARK4 has been proposed to contribute to neurofibrillary tangle formation in Alzheimer's disease. The crystal structure of the catalytic and ubiquitin-associated domains of MARK4 with a potent pyrazolopyrimidine inhibitor has been determined to 2.8 Å resolution with an Rwork of 22.8%. The overall structure of MARK4 is similar to those of the other known MARK isoforms. The inhibitor is located in the ATP-binding site, with the pyrazolopyrimidine group interacting with the inter-lobe hinge region while the aminocyclohexane moiety interacts with the catalytic loop and the DFG motif, forcing the activation loop out of the ATP-binding pocket.
- Published
- 2016
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