Raymond C. Stevens

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Raymond C. Stevens (born 1963) is an American chemist and structural biologist.

Biography[edit]

Stevens was born into a military family. In 1969 his father died in the Air Force, and his mother took several part-time jobs to support the family. He was raised in Auburn, Maine.

In 1980, Stevens joined the Army under their split option training program and conducted basic training at Fort Dix, New Jersey and advanced individual training at Fort Sam Houston, Texas. While engaged in his military service, Stevens entered the University of Southern Maine in the Computer Science program in 1981. However, an enthusiastic professor (John Ricci) converted him to the study of Chemistry. He spent two summers working as an intern at the Brookhaven National Laboratory in Long Island with Professor Ricci, and Drs. Thomas Koetzle and Dick McMullan, where he first learned how to determine the molecular structure of compounds by X-ray and neutron diffraction. While there he also met a University of Southern California research team led by Dr. Robert Bau; after he obtained a Bachelor of Science degree in Chemistry at USM, he entered the University of Southern California in pursuit of a Doctor of Philosophy degree in Chemistry working with Professors Robert Bau and George Olah. He completed his Ph.D. in 26 months, graduating in 1988.[1]

Although science is a major part of his life, Stevens climbs mountains with his wife and children and runs ultramarathons including the Vermont 100 Mile Endurance Run[2] and American River 50 Mile Endurance Run,[3] and in 2011 he successfully completed the 156 mile Marathon des Sables[4] across the Moroccan Sahara Desert.

Scientific career[edit]

After obtaining his Ph.D., Stevens accepted a postdoctoral position in 1988 in the lab of Nobel Laureate William N. Lipscomb, Jr. in the chemistry department at Harvard University where he focused on the large allosteric enzyme aspartate carbamoyltransferase.[5][6][7][8][9][10][11][12][13] In 1991, he accepted a tenure-track position at the University of California, Berkeley in the chemistry department with a joint appointment in neurobiology. His initial research as an assistant professor focused on structural neurobiology and immunology, combining chemistry, structural biology and protein chemistry with a specific biological interest in understanding how the G protein-coupled receptor (GPCR) superfamily works. A seminal collaboration for Stevens was with Professor Peter G. Schultz where they jointly published a series of Science and Nature papers describing the immunological evolution of antibodies through careful structural studies.[14][15][16][17] In 1999, Stevens left Berkeley to take a tenured position at The Scripps Research Institute and is currently a Professor in the Departments of Molecular Biology and Chemistry at The Scripps Research Institute in La Jolla, California. While at The Scripps Research Institute, Stevens has helped to found and establish the Joint Center for Structural Genomics,[18] Joint Center for Innovative Membrane Protein Technologies,[19] and the GPCR Network,[20] all funded by the National Institutes of Health with direct guidance from NIGMS.

Stevens is known for obtaining the structures of many biologically significant proteins and his technological innovations. He is considered a pioneer of high-throughput x-ray crystallography. In October 2007, Stevens and colleagues published the first high-resolution structure of a human GPCR.[21][22] Stevens has also published multiple reports that have been called into question by the scientific community leading to partial and full retractions, including two different structures of ligand-bound clostridial neurotoxins.[23][24]

The β2-adrenergic receptor work was quickly followed up by the determination of the structure of the human A2A adenosine receptor structure,[25] also known as the caffeine receptor. In 2010, the structures of the human chemokine CXCR4 receptor (HIV co-receptor),[26] the human dopamine D3 receptor[27] and the human Histamine H1 receptor [28] were published. In addition to these inactive-state structures, Stevens and colleagues solved the structure of an agonist-bound A2A adenosine receptor.[29] More recently, the first structure of a lipid-activated GPCR, the sphingolipid S1P1 receptor,[30] the human kappa-opioid receptor,[31] and the human nociceptin/orphanin FQ peptide opioid receptor[32] were solved.

In combination with the structural studies, working with the computational biology community to conduct GPCR Dock 2008[33] and GPCR Dock 2010[34] has helped to evaluate where the field is at, and functional studies using HDX[35] and NMR are conducted by Stevens and collaborators to understand how the receptors work at the molecular level, and what fundamental and basic insights can be gained towards developing therapeutic drugs.

Structure based drug discovery[edit]

In 1992, Stevens worked with researchers at Gilead on the structural studies of neuraminidase inhibitors that eventually became Tamiflu,[36][37][38] and later partnered with Roche. After the initial experience with structure based drug discovery from 1992–1997 with Gilead and Tamiflu, Stevens focused on understanding the basic mechanism of how BotoxTM (botulinum toxin) works, and on ways to use this scaffold for next generation protein therapeutics. In parallel to the work on botulinum toxin, Stevens worked on the enzymes involved in the catecholamine biosynthetic pathway, specifically the three aromatic amino acid hydroxylases including phenylalanine hydroxylase. From 2000–2010, Stevens has worked with BioMarin Pharmaceutical to develop KuvanTM (tetrahydrobiopterin) and assisted in the design and development of PEG-PAL (pegylated Phenylalanine ammonia-lyase) as treatments for mild and classical phenylketonuria (PKU).[39][40][41]

Biotechnology Startups[edit]

Stevens has started three biotechnology companies (Syrrx (1999), MemRx (2002), Receptos (2009), and RuiYi (2011)), all focused on structure based drug discovery and each company started with one of his former Ph.D. students. The company Syrrx, started with UC-Berkeley Ph.D. student Nathaniel David and colleague Peter G. Schultz, was acquired by Takeda Pharmaceuticals in 2005 for the high-throughput structure based drug discovery platform, and because of a phase II clinical candidate alogliptin known to inhibit the enzyme DPPIV and is now an approved drug in Japan known as Nesina. MemRx, started with Ph.D. student Mike Hanson and Jun Yoon, was acquired by Sagres Discovery in 2003 for the membrane protein expression technologies, and the combined entity was later acquired by Novartis in 2005. Receptos,[42] started with Ph.D. students Mike Hanson, Chris Roth and staff scientist Mark Griffith along with TSRI colleague Hugh Rosen, continues to be an independent and private biotechnology company focused on GPCR structure based drug discovery with a primary interest in inflammation and oncology and recently completed Phase I clinical trials on their first compound. In 2011, Stevens and his former TSRI graduate student Xu Fei started RuiYi, a biologics GPCR company located in Shanghai, China. The company was acquired by Anaphore in 2012.

Philanthropy[edit]

The Professor Emeritus John Ricci Undergraduate Fellowships[edit]

Established by Stevens to honor USM Professor Emeritus John Ricci and his innovative educational program at Brookhaven National Laboratory, these fellowships offer a unique opportunity for USM undergraduates to pursue research at The Scripps Research Institute in La Jolla, California, one of the world's most prestigious biomedical research institutions.[43]

The Robert Bau Endowed Graduate Fellowship[edit]

Established by Stevens and Charles McKenna in 2010 to honor USC distinguished professor Robert Bau after his death in December 2008, the fellowship proposes to help celebrate Professor Bau's life and honor his extraordinary mentorship by linking him to new generations of young chemists at USC.[44]

References[edit]

  1. ^ Fast-Tracking Lifesaving Discoveries, USC Newsletter, 1 October 2007
  2. ^ Vermont100 race results 2006)
  3. ^ American River 50 Miler race results
  4. ^ [1]
  5. ^ Stevens, R. C., & Lipscomb, W. N., "Allosteric Enzymes" Eds., R. Diamond, T. F. Koetzle, K. Prout, & J. Richardson, Molecular Structures in Biology (Oxford, UK: Oxford University Press, 1993) pp. 223–259.
  6. ^ Stebbins, J. W., Robertson, D. E., Roberts, M. F., Stevens, R. C., Lipscomb, W. N., & Kantrowitz, E. R., "Arginine 54 in the active site of Escherichia coli aspartate transcarbamoylase is critical for catalysis: A site-specific mutagenesis, NMR, and X-ray crystallographic study," Prot. Sci. 1, 1435–1446 (1992).
  7. ^ Stevens, R. C., & Lipscomb, W. N., "A molecular mechanism for pyrimidine and purine nucleotide control of aspartate transcarbamylase," Proc. Natl. Acad. Sci. USA 89, 5281–5285 (1992).
  8. ^ Stevens, R. C., Reinisch, K. M., & Lipscomb, W. N., "Molecular Structure of Bacillus subtilis Aspartate transcarbamoylase at 3.0 A Resolution," Proc. Natl. Acad. Sci. USA 88, 6087–6091 (1991).
  9. ^ Stevens, R. C., Chook, Y. M., Cho, C. Y., Lipscomb, W. N., & Kantrowitz, E. R., "Escherichia coli aspartate carbamoyltransferase: The probing of crystal structure analysis via site-specific mutagenesis," Protein Engineering 4, 391–408 (1991).
  10. ^ Gouaux, J. E., Stevens, R. C., & Lipscomb, W. N., "Crystal Structures of Aspartate Carbamoyltransferase Li gated with Phosphonoacetamide, Malonate and CTP or ATP at 2.8-A Resolution and Neutral pH," Biochemistry 29, 7702–7715 (1990).
  11. ^ Stevens, R. C., J.E. Gouaux, & Lipscomb, W. N., "Structural Consequences of Effector Binding to the T State of Aspartate Carbamoyltransferase Crystal Structures of the Unligated and ATP- and CTP-Complexed Enzymes at 2.6-A Resolution," Biochemistry 29, 7691–7701 (1990).
  12. ^ Stevens, R. C., & Lipscomb, W. N., "Allosteric control of quaternary states in E. coli aspartate transcarbamylase," Biochemistry and Biophysics Research Communications 171, 1312–1318 (1990).
  13. ^ Gouaux, J. E., Stevens, R. C., Ke, H., & Lipscomb, W. N., "Crystal structure of the Glu-239 to Gln mutant of aspartate carbamoyltransferase at 3.1 A resolution: An intermediate quaternary structure," Proc. Natl. Acad. Sci. USA 86, 8212–8216 (1989).
  14. ^ H. D. Ulrich, E. Mundorff, B. D. Santarsiero, E. M. Driggers, R. C. Stevens and P. G. Schultz (1997) The interplay between binding energy and catalysis in the evolution of a catalytic antibody Nature 389: 271–5
  15. ^ G. J. Wedemayer, P. A. Patten, L. H. Wang, P. G. Schultz and R. C. Stevens (1997) Structural insights into the evolution of an antibody combining site Science 276: 1665–9
  16. ^ F. E. Romesberg, B. Spiller, P. G. Schultz and R. C. Stevens (1998) Immunological origins of binding and catalysis in a Diels-Alderase antibody Science 279: 1929–33
  17. ^ A. Simeonov, M. Matsushita, E. A. Juban, E. H. Thompson, T. Z. Hoffman, A. E. t. Beuscher, M. J. Taylor, P. Wirsching, W. Rettig, J. K. McCusker, R. C. Stevens, D. P. Millar, P. G. Schultz, R. A. Lerner and K. D. Janda (2000) Blue-fluorescent antibodies Science 290: 307–13
  18. ^ www.jcsg.org
  19. ^ jcimpt.scripps.edu
  20. ^ cmpd.scripps.edu
  21. ^ USC College : News : October 2007 : Raymond Stevens
  22. ^ V. Cherezov, D. M. Rosenbaum, M. A. Hanson, S. G. Rasmussen, F. S. Thian, T. S. Kobilka, H. J. Choi, P. Kuhn, W. I. Weis, B. K. Kobilka and R. C. Stevens (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor Science 318: 1258–65.
  23. ^ M. A. Hanson, R. C. Stevens (2009) Retraction: Cocrystal structure of synaptobrevin-II bound to botulinum neurotoxin type B at 2.0 A resolution Nat Struct Mol Biol. 16(7):795.
  24. ^ M. A. Hanson, T. K. Oost , C. Sukonpan , D. H. Rich ,R. C. Stevens (2002) Structural Basis for BABIM Inhibition of Botulinum Neurotoxin Type B Protease [J. Am. Chem. Soc. 2000, 122, 11268−11269] J. Am. Chem. Soc. 124(34):10248–10248
  25. ^ V. P. Jaakola, M. T. Griffith, M. A. Hanson, V. Cherezov, E. Y. Chien, J. R. Lane, A. P. Ijzerman and R. C. Stevens (2008) The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist, Science 322: 1211–7
  26. ^ 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).
  27. ^ 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).
  28. ^ 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, S. Iwata. “Structure of the human histamine H1 receptor in complex with doxepin” Nature 475, 65-70 (2011).
  29. ^ F. Xu, H. Wu, V. Katritch, G.W. Han, K.A. Jacobson, Z.-G. Gao, V. Cherezov, R.C. Stevens “Structure of an agonist-bound human A2A adenosine receptor” Science 332, 322-327 (2011).
  30. ^ M.A. Hanson, C.B. Roth, E. Jo, M.T. Griffith, F.L. Scott, G. Reinhart, H. Desale, B. Clemons, S.M. Cahalan, S.C. Schuerer, M.G. Sanna, G.W. Han, P. Kuhn, H. Rosen, R.C. Stevens. “Crystal structure of a lipid G protein-coupled receptor” Science 335, 851-855 (2012).
  31. ^ H. Wu, D. Wacker, M. Mileni, V. Katritch, G.W. Han, E. Vardy, W. Liu, A.A. Thompson, X.-P. Huang, F.I. Carroll, S.W. Mascarella, R.B. Westkaemper, P.D. Mosier, B.L. Roth, V. Cherezov, R.C. Stevens. “Structure of the human kappa opioid receptor in complex with JDTic” Nature 485, 327-332 (2012).
  32. ^ A.A. Thompson, E. Chun, W. Liu, V. Katritch, E. Vardy, H. Wu, C. Trapella, X.-P. Huang, R. Guerrini, G. Calo, B.L. Roth, V. Cherezov, R.C. Stevens “Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic” Nature, 485, 395-399 (2012).
  33. ^ 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).
  34. ^ I. Kufareva, M. Rueda, V. Katritch, participants of GPCR Dock 2010, R.C. Stevens, R. Abagyan. “Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment” Structure 19, 1108-1126 (2011).
  35. ^ G.M. West, E.Y. Chien, V. Katritch, J. Gatchalian, M.J. Chalmers, R.C. Stevens, P.R. Griffin. “Ligand-dependent perturbation of the conformational ensemble for the GPCR β(2) adrenergic receptor revealed by HDX” Structure. Sept 1 (2011) [Epub ahead of print].
  36. ^ C. U. Kim, W. Lew, M. A. Williams, H. Liu, L. Zhang, S. Swaminathan, N. Bischofberger, M. S. Chen, D. B. Mendel, C. Y. Tai, W. G. Laver and R. C. Stevens (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity J Am Chem Soc 119: 681–90;
  37. ^ M. A. Williams, W. Lew, D. B. Mendel, C. Y. Tai, P. A. Escarpe, W. G. Laver, R. C. Stevens and C. U. Kim (1997) Structure-activity relationships of carbocyclic influenza neuraminidase inhibitors Bioorg Med Chem Lett 7: 1837–1842;
  38. ^ C. U. Kim, W. Lew, M. A. Williams, H. Wu, L. Zhang, X. Chen, P. A. Escarpe, D. B. Mendel, W. G. Laver and R. C. Stevens (1998) Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors J Med Chem 41: 2451–60.
  39. ^ H. Erlandsen and R. C. Stevens (1999) The structural basis of phenylketonuria Mol Genet Metab 68: 103–25
  40. ^ L. Wang, A. Gamez, H. Archer, E. E. Abola, C. N. Sarkissian, P. Fitzpatrick, D. Wendt, Y. Zhang, M. Vellard, J. Bliesath, S. M. Bell, J. F. Lemontt, C. R. Scriver and R. C. Stevens (2008) Structural and biochemical characterization of the therapeutic Anabaena variabilis phenylalanine ammonia lyase J Mol Biol 380: 623–35.
  41. ^ T. S. Kang, L. Wang, C. N. Sarkissian, A. Gamez, C. R. Scriver and R. C. Stevens (2010) Converting an injectable protein therapeutic into an oral form: Phenylalanine ammonia lyase for phenylketonuria, Mol Genet Metab 99: 4–9.
  42. ^ www.receptos.com
  43. ^ TSRI Stevens Lab: John Ricci Undergraduate Fellowship
  44. ^ USC Department of Chemistry: In Memoriaum-Robert Bau