CURRENT STRUCTURAL PROJECTS

 Dihydrofolate reductase (DHFR) inhibitor complexes

• Pneumocystis jirovecii DHFR – the cause of Pneumocystis pneumonia (PcP) in   AIDS and immunocompromised patients
• Mutagenesis of active site residues in human, Pnuemocystis carinii and   Pneumocystis jirovecii DHFRs to understand their role in selectivity and drug   resistance
• Mutagenesis of pjDHFR to map the mutations observed in clinical isolates of   patients who are trimethoprim resistant
• 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 pronucleotide 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 their interactions.

Type II heat-labile enterotoxin B pentamer (LT-II-bB₅) interactions with Toll-like receptors TLR2/TLR1

• B pentamer mutants that modify Toll-like receptor interactions
• Small angle X-ray solution scattering (SAXS) data to map the molecular surface profile of TLR-B pentamer interactions
• Crystal complexes of B-pentamer and TLR to map specific interactions

Complexes of human Topoisomerase I with human papillomavirus (HPV) E1 DNA helicase

• Small angle X-ray solution scattering (SAXS) data to map the molecular surface profile of TopoI and the GST-E1 peptide to determine those residues that recognize E1 binding
• Crystal complexes of TopoI and GST-E1 to map specific interactions
• Use structural data to design novel peptide disruptors of the TopoI –E1 interactions as antiviral therapeutics

      • Recent data shows that RGD peptides block hormone binding and that thyroacetic acid inhibits thyroxine-induced cell
        signaling activity
     • Models suggest that the hormone interaction site is located near the RGD recognition site on integrin alphaV and beta3