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Faculty
Raymond Stevens
Professor
Department of Molecular Biology
TSRI - 1999
Joint Appointments CHEMISTRY
Education
B.A., University of Southern Maine, 1986;
Ph.D., University of Southern California, 1988;
National Institutes of Health Postdoctoral Fellowship, Harvard University, 1989.
Awards & Activities
Sidhu Award from Pittsburgh Diffraction Society, 1992;
National Science Foundation Young Investigator Award, 1994;
Beckman Foundation, Young Investigator Award, 1994;
Lawrence Berkeley Laboratory Outstanding Performance Award, 1995;
Society of Bioinorganic Chemistry Award, "Metals in Biology" Gordon Conference, 1997;
Jouan Robotics Award 2003. Founding Scientist Syrrx, Inc. (1999) and MemRx Corporation (2003), acquired by Chiron Corporation.
Member, Editorial Boards: Protein Expression and Purification, 2001-present; Biodrugs, 2001-present; Drug Discovery Today, 2002-present; The Protein Journal, 2004-present.
Research Focus
Structural Neurobiology
Although we have developed high-throughput methods to accelerate the determination of protein structures, our primary interest is applying these tools to study the chemistry and biology of neurotransmission and of diseases that affect neurobiology. Our goals are to understand how neuronal cells function on a molecular level and, on the basis of that understanding, create new molecules and materials that mimic neuronal signal transduction and recognition.
Neurotransmitter Biosynthesis
We are using the high-throughput methods to determine the inclusive structures of complete biochemical pathways, in order to understand the mechanistic details of each individual enzymatic reaction at the atomic level.
Phenylketonuria (PKU)
Recent clinical studies suggest that some patients with the metabolic disease PKU are responsiveness to the natural cofactor to phenylalanine hydroxylase, tetrahydrobiopterin. We are doing studies to correlate how structure can be used to predict which patients with PKU most likely will respond to treatment with this cofactor. In addition, we are initiating studies in PKU model mice of enzyme replacement therapy based on administration of an altered form of Phenylalanine Ammonia Lyase (PAL), with modifications to the enzyme guided by results of our structural and biochemical studies.
Neurotoxins
RWe have previously determined the structures of the 900 kD complex form of botulinum toxin, 150 kD holotoxin form, the catalytic domain, the catalytic domain bound to substrates and inhibitors, and recently the toxin bound to its cell surface receptor. These structures are being used to understand the toxin’s mechanism of action and may be useful in determining additional therapeutic applications for the toxin.
Neuronal Receptors and Enzymes
A major effort is underway to determine the structure of the membrane proteins such as G-protein coupled receptors (GPCRs), nicotinic acetylcholine receptor and connexin in collaboration with the Yeager and Kuhn laboratories (Cell Biology) at TSRI. In an ongoing project with the Cravatt laboratory (Cell Biology), we have solved the structure of the membrane protein FAAH known to degrade cannabinoids. Given our knowledge of the 3-D structure, we are now actively trying to understand how the enzyme works as a basic level, and towards potential drug discovery.
Selected References
A. Gámez, C.N. Sarkissian, L. Wang, W. Kim, M. Straub, M.G. Patch, L. Chen, S. Striepeke, P. Fitzpatrick, J.F. Lemontt, C. O’Neill, C.R. Scriver, R.C. Stevens. “Development of pegylated forms of recombinant Rhodosporidium toruloides phenylalanine ammonia-lyase for the treatment of classical phenylketonuria” Mol. Ther., 11, 986-989 (2005). doi:10.1016/j.ymthe.2005.02.013
L. Wang, A. Gamez, C.N. Sarkissian, M. Straub, M.G. Patch, G.W. Han, S. Striepeke, P. Fitzpatrick, C.R. Scriver, R.C. Stevens. “Structure-based chemical modification strategy for enzyme replacement treatment of phenylketonuria” Mol. Genet. Metab. 86, 134-140 (2005). doi:10.1016/j.ymgme.2005.05.012
Q. Chai, J.W. Arndt, M. Dong, W.H. Tepp, E.A. Johnson, E.R. Chapman, R.C. Stevens. “Structural basis of cell surface receptor recognition by botulinum neurotoxin B” Nature 444, 1096-1100 (2006). DOI:10.1038/nature05411
C. Garcia-Rodriguez, R. Levy, J.W. Arndt, C.M. Forsyth, A. Razai, J. Lou, I, Geren, R.C. Stevens, J.D. Marks. “Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin” Nature Biotechnol. 25, 107-116 (2007). DOI:10.1038/nbt1269
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