Ph.D. Biochemistry, Washington State University 2002
B.S. Biochemistry, University of New Mexico 1996
We seek to advance technology and approaches that accelerate the development of drugs to treat major diseases such as cancer, heart disease and AIDs. To accomplish this goal, our laboratory uses biophysical techniques such as solution NMR, computer modeling and fluorescence spectroscopy to study drugs. We are particularly interested in studying drugs with membrane-bound proteins. These proteins often serve as drug targets for human disease and have numerous important biological functions such as cell signaling, transport and immune recognition. Specifically, we study drug interactions with the multiple drug resistance (MDR) transporter because it:
- Drives anti-cancer drug resistance in ~50% of cancerous tumors.
- Serves to protect reservoirs of HIV virus in the brain, central nervous system (CNS) and testes.
- Causes adverse drug reactions (ADR) from the treatment of heart disease.
- Has been implicated in early-onset Parkinson’s and Alzheimer’s diseases.
We aim to perform these studies relatively rapidly by using already solved protein X-ray and NMR structures (currently, ~125,000) combined with experimentally determined restraints. This approach is considerably more efficient than solving drug-bound protein structures from scratch using traditional protein NMR and X-ray crystallography, which can take months or years to accomplish. A major innovation of our laboratory is that the drug interactions with the transporter are investigated with the proteins embedded in a lipid bilayer under physiological conditions and temperature. We are also collaborating with other renowned laboratories to explore these interactions. The conformation of the MDR transporter in a lipid bilayer is being determined using a state-of-the-art ultrastable atomic force microscope (AFM) from Dr. Gavin M. King’s laboratory at the University of Missouri. This cutting-edge instrument in Dr. King’s laboratory will literally allow us to make movies of individual MDR transporter molecules in a lipid bilayer. We are investigating the dynamics of the MDR transporter embedded in a membrane through molecular dynamics computer simulations by Dr. Megan O’Mara from Australian National University. By combining solution NMR, AFM and computer modeling results from these laboratories, this multidisciplinary/multilaboratory approach will provide us with an unprecedented level of structural and dynamic detail of MDR transporters.
We are very optimistic that this approach will pave the way for future investigations of difficult to study membrane-bound drug targets. In terms of cancer, we are particularly interested in the potential of studying drug interactions with the membrane-bound Ras oncoproteins because they are found in many human cancers and they play a major role in cell signaling and cancer growth. We are also excited by the potential to apply these approaches to the epithelial sodium channel, which is a target for cardiovascular therapeutics. For drugs used to treat neurological diseases, these technologies can also be applied to receptors involved in neurotransmission, such as the GABAA receptor.
In addition to these research goals, we are developing creative and novel teaching methods to train students of different skill levels in my laboratory. To ensure the success of these students, we put considerable effort into their professional development, including having them meet with world-renowned scientists at national and international conferences. Achieving these research and teaching goals will not only advance medicine and improve drug therapies, but will also prepare students well for industry or academic careers in the 21st century.
If you would like more information about my laboratory, please go to www.pharmwiki.org.
- Best Speech Award, Toastmasters International-Stadium Chapter, San Diego, CA, 2011
- Best Table Topics and Best Speech Awards, Toastmasters International-Stadium Chapter, San Diego, CA, 2010
- Poster finalist, International Society for the Study of Xenobiotics (ISSX) Symposium, Maui, HI, 2005
Ledwitch, K. V., Barnes, R. W., and Roberts, A. G.* (2016) Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein. Biosci. Rep. 36, 1-14, Impact Factor = 2.446.
Ledwitch, K. V., Gibbs, M. E., Barnes, R. W., and Roberts, A. G.* (2016) Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein. Biochem. Pharmacol. 118,96-108, Impact Factor = 5.009.
Ledwitch, K. V., and Roberts, A. G.* (2016) Cardiovascular ion channel inhibitor drug-drug interactions with P-glycoprotein. AAPS J, Impact Factor = 3.799.
Roberts, A. G., Katayama, J., Kaspera, R., Ledwitch, K. V., Le Trong, I., Stenkamp, R. E., Thompson, J. A., and Totah, R. A. (2015) The role of cytochrome P450 BM3 phenylalanine-87 and threonine-268 in binding organic hydroperoxides. Biochim. Biophys. Acta 1860, 669-677. PMID: 26723172.
Shimshoni, J. A., Roberts, A. G., Scian, M., Topletz, A. R., Blankert, S. A., Halpert, J. R., Nelson, W. L., Isoherranen, N. Stereoselective Formation and Metabolism of 4-Hydroxy-Retinoic Acid Enantiomers by Cytochrome P450 Enzymes. Journal of Biological Chemistry, 2012. 50. 42223-42232.
Zhao, C. Gao, Q., Roberts, A. G., Shaffer, S. A. Doneanu, C. E., Xue, S., Goodlett, D. R., Nelson, S. D., Atkins, W. M. Cross-Linking Mass Spectrometry and Mutagenesis Confirm the Functional Importance of Surface Interactions between CYP3A4 and Holo/Apo Cytochrome b5. Biochemistry, 2012. 51. 9488-9500.
Roberts, A.G., Sjögren, S.E.A., Fomina, N., Vuc, K.T., Almutairi, A. and Halpert, J.R., NMR-Derived Models of Amidopyrine and its Metabolites Complexed to Rabbit Cytochrome P450 2B4 Reveals a Structural Mechanism of Sequential N-Dealkylation. Biochemistry, 2011. 50, 2123-2134.
Roberts, A. G., Cheesman, M. J., Primak, A., Bowman, M. K., Atkins, W. M., and Rettie, A. E. Intramolecular Heme Ligation of the Cytochrome P450 2C9 R108H Mutant Demonstrates Pronounced Conformational Flexibility of the B-C Loop Region: Implications for Substrate Binding, Biochemistry, 2010. 49, 8700-8708.
Gay, S. C, Roberts, A. G., and Halpert, J. R. Structural features of cytochromes P450 and ligands that affect drug metabolism as revealed by X-ray crystallography and NMR, Future Medicinal Chemistry, 2010. 2, 1451-1468.
Gay, S. C., Roberts, A. G., Maekawa, K., Talakad, J. C., Hong, W. X., Zhang, Q., Stout, C. D., and Halpert, J. R. Structures of cytochrome P450 2B4 complexed with the antiplatelet drugs ticlopidine and clopidogrel, Biochemistry, 2010. 49, 8709-8720.
Wilderman, P. R., Shah, M. B., Liu, T., Li, S., Hsu, S., Roberts, A. G., Goodlett, D. R., Zhang, Q., Woods, V. L., Jr., Stout, C. D., and Halpert, J. R. Plasticity of cytochrome P450 2B4 as investigated by hydrogen-deuterium exchange mass spectrometry and X-Ray crystallography, Journal of Biological Chemistry, 2010. 49, 38602-38611.