Understanding the Switch between Enzyme and Signaling Behaviours in Human Group IIA Secreted Phospholipase A2 by Inhibitory Intervention
The principles of soluble protein structure and ligand docking are applied to structure analysis of membrane bound protein receptors and receptor ligand complexes.
Secreted phospholipase A2 (sPLA2) enzymes regulate cytokine-mediated inflammatory pathways in vitro and in vivo, and may be potential targets for the treatment of certain types of inflammation and cancer. Some of these enzymes are bifunctional with both catalytic and non-catalytic signalling functions. We have demonstrated aspects of the mode of action of three classes of inhibitor: catalytic activity only, dual function and signalling only. Structure-based design of selective inhibitors of sPLA2 function provides a pharmacological approach to understanding these disease states and ultimately, the possibility for therapeutic interventions. The design approach is supported with screening assays of human cPLA2 and sPLA2s, in cell based assays and catalytic activity assays to analyze selectivity and observe inhibitor effects. Our studies on human Group IIA secreted Phospholipase A2 (GIIA), including protein-inhibitor structure studies, have now been deposited at the Protein Data Bank (see PDB IDs 3U8B, 3U8D, 3U8H, 3U8I). This work is with our collaborator, Dr Kieran Scott, and as well there is the possibility of collaborations in the USA.
Techniques with the potential to be used will are enzyme and cell-based assays, molecular biology, bioinformatics, microscopies, X-ray crystallography, molecular modeling; aspects may be suitable as Honours projects.
Want to find out more?
Bioinformatics, sequence analysis, Crystallisation, protein structure, drug design, Proteins, inhibitors, rational drug design, Cancer, Prostate Cancer, inflammation, cardiovascular disease, phospholipase, Phospholipase A2, GIIA
The opportunity ID for this research opportunity is: 1579
Other opportunities with Dr W Bret Church
- Structure-based drug design with Kynurenine Aminotransferase-I
- Informatics and Bioinformatics-based Approaches to Protein-Ligand Interaction
- Structure-based drug design with Soluble Epoxide Hydrolase
- The HAMLET molecular species with anticancer properties
- Medicinal and Pharmaceutical Chemistry — Design, Synthesis and Testing of New Anti-Bacterial Agents