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.
Acta Crystallographica. Section D, Biological Crystallography
|February 25, 2009
Summary
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.
Related Concept Videos
01:17The Extrinsic Apoptotic Pathway
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
02:54Protein Kinases and Phosphatases
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:30Overview of Cell Death
Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the 20th century...
01:24Caspases
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.