Structural insight into nucleotide recognition by human death-associated protein kinase
Laurie K McNamara1, D Martin Watterson, Joseph S Brunzelle
1Center for Drug Discovery and Chemical Biology, Northwestern University, Chicago, Illinois 60611, USA.
Abstract:
Death-associated protein kinase (DAPK) is a member of the Ca(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(2+) at 1.85 A 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(2+) was compared with a newly determined DAPK-AMP-PNP-Mg(2+) structure and the previously determined apo DAPK structure (PDB code 1jks). The comparison shows that nucleotide-induced changes are localized to the glycine-rich loop region of DAPK.
Insights
Structural insights into Death-associated protein kinase (DAPK) reveal how it binds nucleotides. This understanding is crucial for developing DAPK inhibitors for neurodegenerative disorders.
Area of Science:
- Biochemistry
- Structural Biology
- Neuroscience
Background:
- Death-associated protein kinase (DAPK) is a serine/threonine kinase involved in apoptosis.
- DAPK is a drug discovery target for neurodegenerative disorders due to its role in neuronal death.
Purpose of the Study:
- To understand nucleotide recognition by DAPK.
- To gain insights into DAPK's catalytic mechanism.
Main Methods:
- Crystal structure determination of human DAPK in complex with ADP and Mg(2+) at 1.85 Å resolution.
- Comparison of DAPK-ADP-Mg(2+) structure with DAPK-AMP-PNP-Mg(2+) and apo DAPK structures.
Main Results:
- The crystal structure of human DAPK complexed with ADP and Mg(2+) was solved.
- Nucleotide binding induces localized changes in the glycine-rich loop region of DAPK.
Conclusions:
- Structural data provides a basis for understanding DAPK nucleotide binding.
- Insights into DAPK catalysis can inform the design of novel therapeutics for neurodegenerative diseases.
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