Structural insight into nucleotide recognition by human death-associated protein kinase

Journal Article · Sun Mar 01 04:00:00 EST 2009 · Acta Crystallographica. Section D: Biological Crystallography

DOI:https://doi.org/10.1107/S0907444908043679· OSTI ID:22347975

McNamara, Laurie K. ^[1]; Watterson, D. Martin ^[1]

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1. Center for Drug Discovery and Chemical Biology, Northwestern University, Chicago, Illinois 60611 (United States)

The crystal structures of DAPK–ADP–Mg{sup 2+} and DAPK–AMP-PNP–Mg{sup 2+} complexes were determined at 1.85 and 2.00 Å resolution, respectively. Comparison of the two nucleotide-bound states with apo DAPK revealed localized changes in the glycine-rich loop region that were indicative of a transition from a more open state to a more closed state on binding of the nucleotide substrate and to an intermediate state with the bound nucleotide product. Death-associated protein kinase (DAPK) is a member of the Ca{sup 2+}/calmodulin-regulated family of serine/threonine protein kinases. The role of the kinase activity of DAPK in eukaryotic cell apoptosis and the ability of bioavailable DAPK inhibitors to rescue neuronal death after brain injury have made it a drug-discovery target for neurodegenerative disorders. In order to understand the recognition of nucleotides by DAPK and to gain insight into DAPK catalysis, the crystal structure of human DAPK was solved in complex with ADP and Mg{sup 2+} at 1.85 Å resolution. ADP is a product of the kinase reaction and product release is considered to be the rate-limiting step of protein kinase catalytic cycles. The structure of DAPK–ADP–Mg{sup 2+} was compared with a newly determined DAPK–AMP-PNP–Mg{sup 2+} structure and the previously determined apo DAPK structure (PDB code http://scripts.iucr.org/cgi-bin/cr.cgi?rm). The comparison shows that nucleotide-induced changes are localized to the glycine-rich loop region of DAPK.

• OSTI ID: 22347975
• Journal Information: Acta Crystallographica. Section D: Biological Crystallography, Journal Name: Acta Crystallographica. Section D: Biological Crystallography Journal Issue: Pt 3 Vol. 65; ISSN ABCRE6; ISSN 0907-4449
• Country of Publication: Denmark
• Language: English

Related Subjects

75 CONDENSED MATTER PHYSICS
SUPERCONDUCTIVITY AND SUPERFLUIDITY
BOUND STATE
CATALYSIS
CRYSTAL STRUCTURE
CRYSTALS
GLYCINE
INTERMEDIATE STATE
RESOLUTION
SUBSTRATES