Molecular Biology; Pharmacology; Anti-Retroviral Agents; HIV Reverse Transcriptase; Multifunctional Enzymes
The primary emphasis focuses on developing an understanding of enzymatic reactions and receptor-ligand interactions at a molecular level. The approach is to use a combination of structural techniques including rapid transient kinetics, NMR, and xRay crystallography. This allows a quantitative and structural basis for understanding how proteins work at a molecular level.
Our ultimate goal in this research is to develop an in-depth mechanistic understanding of how enzymes function and thereby provide a more effective means of modulating their function. This approach has been used to examine a number of enzyme mechanisms including EPSP synthase, tryptophan synthase, PABA synthase, LAR-tyrosine phosphatase, and HIV reverse transcriptase. We have recently uncovered some interesting mechanistic features of HIV reverse transcriptase which may ultimately aid in the design of better therapeutic agents for the treatment of AIDS.
Specialized Terms: Enzyme function; Anti-viral agents
Extensive Research Description
Our research is directed toward understanding molecular mechanism of clinically important antimicrobial, anticancer, and antiviral molecular targets with the ultimate goal of developing more effective therapies. Key enzyme targets for the development of therapeutics include: KDO8P synthase (an important target for new antibacterials) and a bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme from parasites (a target for new antiparasitic drugs).
Also ongoing are studies to understanding the molecular mechanisms of normal and aberrant protein signaling and the effects of selectively guided anticancer drugs such as Iressa and Gleevec. Important molecular targets include EGFR, HER-2, PDGFRb, and c-kit receptor tyrosine kinases. Another area of focus involves investigating the mechanisms of HIV reverse transcriptase as well as drug resistance and toxicity that may ultimately aid in the design of better therapeutic agents for the treatment of AIDS.
- Li Z, Song F, Zhuang Z, Dunaway-Mariano D, Anderson KS. Monitoring enzyme catalysis in the multimeric state: direct observation of Arthrobacter 4-hydroxybenzoyl-coenzyme A thioesterase catalytic complexes using time-resolved electrospray ionization mass spectrometry. Anal Biochem. 2009 Jul 25. [Epub ahead of print] PMID: 19635449 [PubMed - as supplied by publisher]
- Bautista AD, Stephens OM, Wang L, Domaoal RA, Anderson KS, Schepartz A. Identification of a beta3-peptide HIV fusion inhibitor with improved potency in live cells. Bioorg Med Chem Lett. 2009 Jul 15;19(14):3736-8. Epub 2009 May 15. PMID: 19497744 [PubMed - in process]
- Nichols SE, Domaoal RA, Thakur VV, Tirado-Rives J, Anderson KS, Jorgensen WL. Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures. J Chem Inf Model. 2009 May;49(5):1272-9. PMID: 19374380 [PubMed - indexed for MEDLINE]
- Furdui, C., Lew, E., Schlessinger, J., and Anderson, K.S. (2006). Autophosphorylation of the kinase domain of FGFR1 is mediated by a sequential and precisely ordered reaction. Molec. Cell 21:711-717
- Basavapathruni, A., et al. (2006). Modulation of HIV-1 synergistic inhibition by reverse transcriptase mutations. Biochem. 45:7334-40.