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, M., Setola, V., Irwin, J., Laggner, C., Abbas, A., Hufesein, S.., Jensen, N., Kuijer, M., Matos, R., Tran, T.B., Whaley, R., Glennon, R.A., Hert, J., Thomas, K.L.H., Edwards, D.D., Shoichet, B.K.* and Roth, B.L*. (2009) Predicting new molecular targets for known drugs. Nature 462: 175-181, 2009. PMC2784146. (*BLR and BKS=Co-Corresponding authors) Abstract
Besnard, J.., Ruda, G.F., Setola, V., Abecassis, K., Rodriguez, R.M., Huang, X-P., Norval, S., Sassano, M.F., Shin, A.I., Webster, L.A., Simeons, F.R.C., Stojanovski, L., Prat, A., Seidah, N.G., Constam, D.B., Bickerton, G.R., Read, K.D., Wetsel, W.C., Gilbert, I.H., Roth, B.L.* and Hopkins, A.L*. (2012) Automated design of ligands with polypharmacology profiles. Nature 492: 215-220. PMID:23235874. (*BLR and ALH=Co-Corresponding Authors). Abstract
Fenalti, G., Giguere, P., Katrich, S., Huang, X-P., Thompson, A., Cherezov, A., Roth, B.L. and Stevensm R.C. (2014) Molecular Control of δ-Opioid Receptor Signaling, Nature, Jan. 12, doi: 10.1038/nature12944. [Epub ahead of print] PMCID:24413399. (*BLR and RCS=Co-corresponding authors). Abstract
Alexander, G.M., Rogan, A.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. Remote control of neuronal activity in transgenic mice expressing evolved G protein coupled receptors. Neuron 63(1):27-39. PMC2751885. Abstract
Wacke, D., Wang, C., Katritch, V., Han, G.W., Huang, X.P., Vardy, E., McCorvy, J.D., Jiang, Y., Chu, M., Siu, F., Liu, W., Xu, H.E., Cherezov, V., Roth, B.L. and Stevens, R.C. (2013) Structural Features for Functional Selectivity at Serotonin Receptors. Science 340(6132): 615-9. PMID:23519210. (*BLR and *RCS=Co-corresponding authors) Abstract