X-Ray Crystallographic Studies of Dyrk1a, a Kinase Linked to Down Syndrome
AuthorGomez Casarez, Axel Omer
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractDown syndrome (DS) is a chromosomal aberration that causes learning disability and neurodegeneration. Previous studies suggest that the overexpression of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) contributes to the early onset of DS symptoms. This study was conducted to find key binding interactions between DYRK1A and both AMP-PNP and the novel inhibitor DYR219. X-ray quality crystals of DYRK1A-AMPPNP and preliminary crystals of DYRK1A-DYR219 complexes were obtained. The crystal structure of the DYRK1A-AMPPNP complex was determined at a resolution of 2.7 Å. The structure identifies residues involved in the binding of AMP-PNP. Ser169, Glu239, and Leu241 form a hydrogen bond network with the ATP analogue. Asn292 and Asp307 coordinate the AMP-PNP molecule via a Mg#$ ion. Finally, a hydrophobic pocket binds the adenine ring of the AMP-PNP molecule. The structure of the DYRK1A-AMPPNP complex was compared with other DYRK1A structures to identify differences in conformation of the protein and ligand binding. ATP binding sites for various kinases from the CMGC group were also compared to identify similarities and differences in the ATP pocket. The structure of the DYRK1A-AMPPNP complex showed a distinct conformation at residue Phe170 and movement in the activation loop. Successful crystallization of the DYRK1A-DYR219 complex should result in a crystal structure and will enable detailed characterization of binding of DYR219 in the ATP pocket. These data are fundamental for the designing of new potent DYRK1A inhibitors.
Degree ProgramHonors College