Department of Pharmacology
Michael Hooker Chair Protein Therapeutics and Translational Proteomics Professor
Division of Medicinal Chemistry and Natural Products, School of Pharmacy
Director, NIMH Psychoactive
- GPCR Structure and Function
- Drug Discovery
GPCR structure and function
G-protein coupled receptors (GPCRs) represent one of the most evolutionarily diverse superfamilies of the human genome. My lab studies all aspects of GPCR structure and function ranging from the atomic-level analysis of ligand-receptor interactions to in vivo studies. Currently we are focused on members of the serotonin (5-hydroxytryptamine; 5-HT) and opioid receptor families and their accessory proteins.
We are actively engaged in drug discovery efforts via the shared resources of the National Institute of Mental Health's Psychoactive Drug Screening Program. Our goals are to discover and develop novel small molecule probes for in vitro and in vivo validation of molecular targets for therapeutic drug discovery. We have particular strengths with GPCR and ion-channels and are gradually expanding our capabilities to, eventually, screen the receptorome (the entire complement of receptors in the genome) and kinome (the entire complement of kinases in the genome) in massively parallel screening campaigns (see figure).
Click above for PubMed publications.
- Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, Hufeisen SJ, Jensen NH, Kuijer MB, Matos RC, Tran TB, Whaley R, Glennon RA, Hert J, Thomas KL, Edwards DD, Shoichet BK, Roth BL. (2009) Predicting new molecular targets for known drugs. Nature 462(7270): 175-181.
- Alexander, G,.M., Rogan, S.C., Abbas, A.I., Armbruster, B.N., Pei, Y., Allen, J.A., Nonneman, R.J., Hartmann, J., Moy, S.S., Nicolelis, M.A., McNamara, J.O., and Roth, B.L. (2009) Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63(1): 27-39. Abstract
- Armbruster, B.N., Li, X., Pausch, M.H., Herlitze, S., and Roth, B.L. (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci USA 104(12): 5163-8. Abstract
- Keiser, M.J., Roth, B.L., Armbruster, B.N., Ernsberger, P., Irwin, J.J., Shoichet, B.K. (2007) Relating protein pharmacology by ligand chemistry. Nature Biotechnolology 25(2): 197-206. Abstract
- Roth, B.L. (2007) Drugs and valvular heart disease. N Engl J Med 356(1): 6-9. Article
- Sheffler, D.J., Kroeze, W.K., Garcia, B.G., Deutch, A.Y., Hufeisen, S.J., Leahy, P., Bruning, J.C., Roth, B.L. (2006) p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling. Proc Natl Acad Sci USA 103(12): 4717-22. Abstract
- O'Connor, K.A., and Roth, B.L. (2005) Finding new tricks for old drugs: an efficient route for public-sector drug discovery. Nat Rev Drug Discovery 4(12): 1005-14. Abstract
- Elphick, G.F., Querbes, W., Jordan, J.A., Gee, G.V., Eash, S., Manley, K., Dugan, A., Stanifer, M., Bhatnagar, A., Kroeze, W., Roth, B.L., and Atwood, W.J.(2004) The human polyoma virus, JCV, uses serotonin receptors to infect cells. Science 306(5700): 1380-1383. Abstract