CURRENT STRUCTURAL PROJECTS

      • Dihydrofolate reductase (DHFR) inhibitor complexes

- Pneumocystis jirovecii DHFR - the cause of PCP in AIDS patients.
- Mutagenesis of active site residues in human, Pneumocystis carinii and Pneumocystis jirocevii DHFRs to understand their role in selectivity and drug resistance.
- E. coli DHFR - homo-bifunctional MTX dimer complexes that form multimeric protein assemblies (nanotubes) as drug delivery systems.

      • Histidine triad nucleotide binding proteins (Hint)

- Nucleoside phosphoramidate and acyl-adenylase hydrolases with substrate specificity between human and bacterial enzymes make them a target for antibacterial pronucleoside drug design.
- Complexes with nucleotide analogues with human / E. coli chimera  to determine mechanism of C-terminal ligand specificity.
- Protein-protein complexes with LysU, LysRS to determine interactions.

         • Beta sliding clamp complexes with polymerase fragments for DNA repair.

- E. coli b sliding clamp is proposed to play an important role in regulating DNA polymerase traffic at the replication fork.
- Mutant forms of b-clamp function in DNA polymerase V-dependent translesion DNA synthesis.
- The H148-R152 to Ala mutant of b-clamp impaired the pol V- dependent translesion DNA synthesis.
- The 148-152 loop is important for translesion DNA synthesis and pol III and pol V interact with non-identical surfaces of the b-clamp

• Computational models of integrin-thyroid hormone interactions to design non-genomic
hormone analogues

- Recent competition data reveal that RGD peptides block hormone binding and that T4 acetic acid inhibits T4-induced MAPK activity
- These data suggest that the hormone interaction site is located near the RGD recognition site on integrin alpha V beta 3

• GTP cyclohydrolase I isoforms and mutants from Drosophila

Structural studies of GTP cyclohydrolase are being carried out to understand how its inhibition relates to Parkinson's disease.

- Our collaborators have a paraquat oxidative stress model in Drosophila that mimics the behavior and cellular responses of Parkinson's disease
- GTP cyclohydrolase I is the rate limiting step in dopamine biosynthesis