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Raymond Stevens, Ph.D.

Professor
Department of Integrative Structural and Computational Biology
California Campus
Laboratory Website
stevens@scripps.edu
(858) 784-9416

Scripps Research Joint Appointments

Department of Chemistry
Faculty, Graduate Program

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.  To date, we have used our basic science knowledge to help and develop a number of therapeutic molecules now on the market or in clinical development.

G-protein coupled receptors

During the past 3 years we have solved the structures of 4 different GPCR’s - adrenaline receptor (b2 adrenergic receptor), caffeine receptor (A2a adenosine receptor), CXCR4 chemokine receptor, and the D3 dopamine receptor.  With a process now in place to understand GPCR structure, we are expanding our scope to understand the mechanism of signal transduction and function of this important protein family through the creation of the GPCR Network (http://gpcr.scripps.edu).  Efforts to develop next generation therapeutics to GPCR’s are in progress in parallel to the basic science questions being pursued.

Education

B.A., Chemistry, University of Southern Maine, 1986
Ph.D., Chemistry, University of Southern California, 1988

Professional Experience

1989-1992 NIH Postdoctoral Fellowship, Chemistry Department, Harvard University. Postdoctoral Advisor: Professor William N. Lipscomb. 1992-2000 Professor of Chemistry, University of California, Berkeley; 2000-present, Professor of Molecular Biology and Chemistry at The Scripps Research Institute; Founder of 4 NIH centers and 3 biotechnology companies.

Awards & Professional 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; Distinguished Alumni Award, University of Southern California, 2005. 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.

Selected References

M.A. Hanson, A. Brooun, K.A. Baker, V.-P. Jaakola, C. Roth, E. Chien, A. Alexandrov, J. Velasquez, L. Davis, M. Griffith, K. Moy, B. Ganser-Pornillos, P. Kuhn, S. Ellis, M. Yeager, and R.C. Stevens “Profiling of membrane protein variants in a baculovirus system by coupling cell-surface detection with small-scale parallel expression” Protein Expr. Purific. 56, 85-92 (2007).

V. Cherezov, D.M. Rosenbaum, M.A. Hanson, S.G.F. Rasmussen, F.S. Thian, T.S. Kobilka, H.-J. Choi, P. Kuhn, W.I. Weis, B.K. Kobilka, R.C. Stevens “High resolution crystal structure of human β2-adrenergic G protein coupled receptor”  Science 318, 1258-1265 (2007).

D.M. Rosenbaum, V. Cherezov, M.A. Hanson, S.G.F. Rasmussen, F.S. Thian, T.S. Kobilka, H.-J. Choi, X.-J. Yao, W.I. Weis, R.C. Stevens, B.K. Kobilka “GPCR engineering provides high resolution structural insights into the function of the β2-adrenergic receptor” Science 318, 1266-1273 (2007).

A.I. Alexandrov, M. Mileni, E.Y.T. Chien, M.A. Hanson, R.C. Stevens “Microscale fluorescent thermal stability assay for membrane proteins” Structure 16, 351-359 (2008).

C.B. Roth, M.A. Hanson, R.C. Stevens “Stabilization of the human β2-adrenergic receptor TM4-TM3-TM5 helix interface by mutagenesis of Glu-1223.41, A critical residue in GPCR structure” J. Mol. Biol. 376, 1305-1319 (2008).

M.A. Hanson, V. Cherezov, C.B. Roth, M.T. Griffith, V.-P. Jaakola, E.Y.T. Chien, J. Velasquez, P. Kuhn, R.C. Stevens “A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor” Structure, 16, 897-905 (2008).

M.A. Hanson, V. Cherezov, C.B. Roth, M.T. Griffith, V.-P. Jaakola, E.Y.T. Chien, J. Velasquez, P. Kuhn, R.C. Stevens “A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor” Structure, 16, 897-905 (2008).

V.P. Jaakola, M.T. Griffith, M.A. Hanson, V. Cherezov, E.Y.T. Chien, J.R. Lane, A.P. IJzerman, R.C. Stevens. “The 2.6Å crystal structure of a human A2A adenosine receptor bound to an antagonist” Science, 322, 1211-1217 (2008).

V. Cherezov, J. Liu, M.T. Griffith, M.A. Hanson, R.C. Stevens. “LCP-FRAP Assay for Pre-Screening Membrane Proteins for in Meso Crystallization” Crystal Growth & Design, 8, 4307-4315 (2008).

M.A. Hanson, R.C. Stevens. “Discovery of new GPCR biology: One receptor structure at a time” Structure 17, 8-14 (2009).

M. Michino, E. Abola, GPCR Assessment Participants, C.L. Brooks, J.S. Dixon, J. Moult, R.C. Stevens. “Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008” Nature Rev. Drug Disc. 8, 455-463 (2009).

V.P. Jaakola, R.C. Stevens. “G Protein-Coupled Receptors” Handbook of Cell Signaling, 2nd Edition, R.A. Bradshaw and E.A. Dennis, Eds., Oxford:Academic Press (2009) pp. 129-138.

V. Cherezov, M.A. Hanson, M.T. Griffith, M.C. Hilgart, R. Sanishvili, V. Nagarajan, S. Stepanov, R.F. Fischetti, P. Kuhn, and R.C. Stevens “Rastering strategy for screening and centering of microcrystal samples of human membrane proteins with a sub 10 micron size X-ray synchrotron beam” J. Royal Society Interface 6 Suppl 5, S587-S597 (2009).

X. Zhang, E.Y. Chien, M.J. Chalmers, B.D. Pascal, J. Gatchalian, R.C. Stevens, P.R. Griffin. “Dynamics of the β2-adrenergic G-protein coupled receptor revealed by hydrogen-deuterium exchange" Anal. Chem. 82, 1100-1108 (2010).

V. Katritch, V.P. Jaakola, J.R. Lane, J. Lin, A.P. IJzerman, M. Yeager, I. Kufareva, R.C. Stevens, R. Abagyan. “Structure-based discovery of novel chemotypes for adenosine  A(2A) receptor antagonists. J. Med. Chem. 53, 1799-1809 (2010).

V.P. Jaakola, J.R. Lane, J.Y. Lin, V. Katritch, A.P. IJzerman, R.C. Stevens. “Ligand binding and subtype selectivity of the human A(2A) adenosine receptor: identification and characterization of essential amino acid residues” J. Biol. Chem. 285, 13032-44 (2010).

W. Liu, M.A. Hanson, R.C. Stevens, V. Cherezov. “LCP-Tm: an assay to measure and understand stability of membrane proteins in a membrane environment” Biophys. J. 98, 1539-1548 (2010).

W.X. Hong, K.A. Baker, X. Ma, R.C. Stevens, M. Yeager, Q. Zhang. “Design, Synthesis, and Properties of Branch-Chained Maltoside Detergents for Stabilization and Crystallization of Integral Membrane Proteins: Human Connexin 26” Langmuir 26, 8690-6 (2010).

M. Michino, J. Chen, R.C. Stevens, C.L. Brooks. “FoldGPCR: structure prediction protocol for the transmembrane domain of G protein-coupled receptors from class A” Proteins 10, 2189-2201 (2010).

V. Cherezov, E. Abola, R.C. Stevens “Toward drug design: Recent progress in the structure determination of GPCRs, a membrane protein family with high potential as pharmaceutical targets” Methods Mol. Biol. 654, 141-168 (2010).

D. Wacker, G. Fentalti, M.A. Brown, V. Katritch, R. Abagyan, V. Cherezov, R.C. Stevens “Conserved binding mode of human β2 adrenergic receptor inverse agonists and antagonist revealed by X-ray crystallography” J. Am. Chem. Soc. 132, 11443-11445 (2010).

C.G. Tate, R.C. Stevens “Growth and excitement in membrane protein structural biology” Curr. Opin. Struct. Biol. 20, 399-400 (2010).

F. Siu, R.C. Stevens “RAMP-ing up Class B GPCR ECD structural coverage” Structure 18, 1067-1068 (2010).

B. Wu, E.Y.T. Chien, C.D. Mol, G. Fenalti, W. Liu, V. Katritch, R. Abagyan, A. Brooun, P. Wells, F.C. Bi, D.J. Hamel, P. Kuhn, T.M. Handel, V. Cherezov, R.C. Stevens “Structures of the CXCR4 chemokine GPCR with small molecule and cyclic peptide antagonists” Science 330, 1066-1071 (2010).

E.Y.T. Chien, W. Liu, Q. Zhao, V. Katritch, G.W. Han, M.A. Hanson, L. Shi, A.H. Newman, J.A. Javitch, V. Cherezov, R.C. Stevens “Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist” Science 330, 1091-1095 (2010).

I. Kufareva, M. Rueda, V. Katritch, R. C. Stevens and R. Abagyan. “Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment” Structure 19, 1108-26 (2011).

T. Shimamura, M. Shiroishi, S. Weyand, H. Tsujimoto, G. Winter, V. Katritch, R. Abagyan, V. Cherezov, W. Liu, G. W. Han, T. Kobayashi, R. C. Stevens and S. Iwata. “Structure of the human histamine H(1) receptor complex with doxepin” Nature 475(7354), 65-70 (2011).

G. M. West, E. Y. Chien, V. Katritch, J. Gatchalian, M. J. Chalmers, R. C. Stevens and P. R. Griffin. “Ligand-Dependent Perturbation of the Conformational Ensemble for the GPCR beta(2) Adrenergic Receptor Revealed by HDX” Structure 19(10), 1424-32 (2011).

F. Xu, W. Liu, M. A. Hanson, R. C. Stevens and V. Cherezov. “Development of an Automated High Throughput LCP-FRAP Assay to Guide Membrane Protein Crystallization in Lipid Mesophases” Cryst Growth Des 11, 1193-1201 (2011).

F. Xu and R. C. Stevens. “Trapping Small Caffeine in a Large GPCR Pocket” Structure 19, 1204-7 (2011).

F. Xu, H. Wu, V. Katritch, G. W. Han, K. A. Jacobson, Z. G. Gao, V. Cherezov and R. C. Stevens “Structure of an agonist-bound human A2A adenosine receptor” Science 332, 322-7 (2011).

Links

Stevens Lab Website

JCIMPT-Complexes

GPCR Network