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Richard W. Roberts

Professor of Chemistry, Chemical Engineering and Materials Science, and Molecular and Computational Biology.
Full Member, USC Norris Cancer Center

Peptide and Protein Engineering via mRNA Display

NIH and Alfred P. Sloan Foundation Postdoctoral Fellow 1993-97 Harvard Medical School/MGH
Ph.D. Biophysical Chemistry, Yale University, 1993
B.S. Chemistry, University of Kansas, 1987
Office: RTH 507
Phone: (213) 821-4132
Fax:
Email: richard.roberts@usc.edu
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Research Focus

 

The Chemical Biology of Protein Synthesis.

Research in the Roberts lab focuses on the protein synthesis machinery both as a tool for polypeptide design and as a target that can be probed using chemical means. A key aspect of my lab's work is peptide and protein design using in vitro selection experiments. Toward this end, we use mRNA display, a technique the PI conceived and implemented to enable polypeptide design (see figure below). This approach allows the lab to create and sieve more than 10 trillion independent peptide or protein sequences for function, the most of any technique currently available. In applying any design approach, it is optimal if key issues, including affinity, specificity, diversity, structure, dynamics, and biological activity can be addressed in a principled way. The lab desires to execute a research program that tackles all of these issues.
Our passion is using the tools of chemistry to understand and control biological processes. We have applied our design approach to address biological control, molecular recognition, stability, and dynamics in RNA-peptide complexes, G proteins and G protein coupled receptors (GPCRs). In the future, our efforts should provide new tools for systems biology and leads for therapeutic development.
mRNA display
mRNA display
. An mRNA template (black line) covalently attached to puromycin is used to program an in vitro translation reaction. After protein synthesis, the puromycin enters the ribosome in cis to form a covalent mRNA-protein fusion.

We are also very interested to re-engineer the protein synthesis machinery to create unnatural mRNA display libraries. This project, a nanoscale engineering effort, works to merge the power of display selections with the flexibility of combinatorial chemistry. To do this, the lab has worked to extend mRNA display beyond the natural genetic code, in an effort to create new and richly diverse compositions of matter for ligand design, drug discovery, and beyond.
In conjunction with our re-engineering efforts, we have become intensely interested in thinking about the ribosome as a target for puromycin analogues. Our work began with efforts to understand the ribosome's substrate specificity. These efforts have also yielded unexpected and exciting new reagents that have enabled us to visualize protein synthesis in vivo in T-cells and neurons with spatial and temporal resolution.

Finally, the PI's intellectual interest in evolution and the origin of life has lead to work on a model for the origin of the ribosome and a proposal for how Darwinian evolution could have begun via coupling genome replication and cellular growth.

Overall, research in the Roberts lab bridges Chemistry, Biology, and Engineering with the goal of bringing new approaches to molecular design, systems biology, and therapeutics. We have pursued these goals in both formal and informal collaborations with other labs including (J. Alberola-Ila, S. Benzer, P. Bjorkman, D. Dougherty, B. Hay, E. Schuman, A. Varshavsky, A. H. Zewail, S. R. Sprang N. Strynadka, J. W. Szostak, and L. Jan).

Selected publications

 
1. 

Steven W. Millward, Stephen V. Fiacco, Ryan J. Austin, and Richard W. Roberts*. "Design of Cyclic Peptides that Bind Protein Surfaces with Antibody-Like Affinity." ACS Chem. Biol. 2 625-34 (2007).

2.

William W. Ja, Anthony West, Sylvia Delker, Pamela Bjorkman, Seymour Benzer, and Richard W. Roberts* "Extension of Drosophila lifespan using a selected peptide inhibitor of the Methuselah G protein-coupled receptor" Nature Chemical Biology 3 415-419 (2007).

3.

C. Anders Olson and Richard W. Roberts* "Design, expression, and stability of a diverse protein library based on the tenth fibronectin type III domain" Protein Science, 16 476-484 (2007).

4.

William W. Ja, Ofer Wiser, Ryan J. Austin, Lily Y.  Jan, Richard W. Roberts* "Turning G proteins on and off:  peptide modulators of signaling" ACS Chemical Biology 1, 570-574 (2006).

5.

Ofer Wiser, Xiang Qian, Melissa Ehlers, William W. Ja, Richard W. Roberts, Eitan Reuveny, Yuh Nung Jan and Lily Yeh Jan* "Modulation of Basal and Receptor-induced GIRK Potassium Channel Activity and Neuronal Excitability by the Mammalian PINS Homolog LGN" Neuron 50 561-73 (2006).

6.

Steven W. Millward, Terry T. Takahashi, Richard W. Roberts.* "A General Route for Post-Translational Cyclization of mRNA Display Libraries." J. Am. Chem. Soc. 127 14142-3 (2005).

7.

Tianbing Xia, Chaozhi Wan, Richard W. Roberts,* Ahmed H. Zewail.* RNA-Protein Recognition: Single-Residue Ultrafast Dynamical Control of Structural Specifcity and Function. Proc Natl Acad Sci 102 13013-18 (2005).

8.

William W. Ja, Richard W. Roberts.* "G Protein-Directed Ligand Discovery with Peptide Combinatorial Libraries." TiBS 30 318-324 (2005).

9.

William W. Ja, Anirban Adhikari, Ryan J. Austin, Stephen R. Sprang, and Richard W. Roberts.* "A Peptide Core Motif for Binding Heterotrimeric G protein Subunits" Journal of Biological Chemistry 280 32057-60 (2005).

10.

William W. Ja and Richard W. Roberts.* "Epitope Mapping Using mRNA Display and a Unidirectional Nested Deletion Library" Protein Engineering, Design, and Selection 18 309-19 (2005).

11.

W. Bryan Smith, Shelley R. Starck, Richard W. Roberts, and Erin M. Schuman.* "Dopaminergic Stimulation of Local Protein Synthesis Enhances Surface Expression of GluR1 and Synaptic Transmission" Neuron 45 765-779 (2005).

12.

Richard W. Roberts.* Engineering Switches, Genetically" Chemistry & Biology 11 1475-1476 (2004); this article is a preview of G. Guntas, S. F. Mitchell, M. Ostermeier "A Molecular Switch Created by In Vitro Recombination of Non-Homologous Genes" Chemistry & Biology 11 1483-87 (2004).

13.

Irene A. Chen, Richard W. Roberts, and Jack W. Szostak.* "Systems-Level Properties of Model Protocells and the Emergence of Darwinian Evolution" Science 305 1474-1476 (2004).

14.

William W. Ja and Richard W. Roberts.* "In Vitro Selection of State-Specific Modulators of G Protein Signaling Using mRNA Display" Biochemistry, 43, 9265-9275 (2004).

15.

Shelley R. Starck, Harry M. Green, Jose Alberola-Ila, and Richard W. Roberts.* "A General Approach to Detect Protein Expression in Vivo Using Fluorescent Puromycin Conjugates" Chemistry & Biology, 11, 999-1008 (2004).

16.

Christine T. Ueda and Richard W. Roberts.* " Analysis of a Long Range Interaction Between Conserved Domains of Human Telomerase RNA," RNA, 10, 139-147 (2004).

17. 

Adam Frankel, Steven W. Millward, and Richard W. Roberts.* "Encodamers: Unnatural Peptide Oligomers Encoded in RNA," Chemistry & Biology, 10, 1043-1050 (2003).

18. 

Ryan J. Austin, Tianbing Xia, Jinsong Ren, Terry T. Takahashi, and Richard W. Roberts.* "Differential Modes of Recognition in N-peptide/BoxB RNA Complexes" Biochemistry, 42, 14957-14967 (2003).

19. 

Jeffrey E. Barrick and Richard W. Roberts.* "Achieving Specificity in Selected and Wild-Type N Peptide-RNA complexes," Biochemistry, 42, 12298-13007 (2003).

20. 

Adam Frankel, Shuwei Li, Shelley R. Starck, and Richard W. Roberts .* "Unnatural RNA Display Libraries," Current Opinion in Structural Biology, 13, 506-512 (2003).

21. 

Tianbing Xia, Adam Frankel, Jinsong Ren, Terry T. Takahashi, and Richard W. Roberts.* "Context and Conformation Dictate Function of a Transcription Antitermination Switch," Nature Structural Biology, 10, 812-819 (2003).

22. 

Tianbing Xia, Chaozhi Wan, Hans-Christian Becker, Adam Frankel, Richard W. Roberts*, and Ahmed H. Zewail.* "The RNA-Protein Complex: Direct Probing of the Interfacial Recognition Dynamics and its Correlation with Biological Functions," Proc. Natl. Acad. Sci. USA, 100, 8119-8123 (2003).

23. 

Shelley R. Starck, Xin Qi, Brett N. Olsen, and Richard W. Roberts.* "The Puromycin Route to Assess Stereo- and Regiochemical Constraints on Peptide Bond Formation in Eukaryotic Ribosomes," J. Am. Chem. Soc., 125, 8090-8091 (2003).

24. 

Adam Frankel and Richard W. Roberts.* "In Vitro Selection for Sense Codon Suppression," RNA, 9, 780-786 (2003).

25. 

Terry T. Takahashi, Ryan Austin, and Richard W. Roberts.* "mRNA Display: Ligand Discovery, Interaction Analysis and Beyond," Trends in Biochemical Sciences, 28, 159-165 (2003).

26. 

Shuwei Li and Richard W. Roberts.* "A Novel Strategy for In Vitro Selection of Peptide-Drug Conjugates," Chemistry & Biology, 10, 233-239 (2003).

27. 

Shuwei Li, Steven W. Millward, Richard W. Roberts.* "In Vitro Selection of mRNA Display Libraries Containing an Unnatural Amino Acid," J. Am Chem. Soc. 124, 9972-9973 (2002).

28. 

Ryan J. Austin, Tianbing Xia, Jinsong Ren, Terry T. Takahashi, Richard W. Roberts.* "Designed Arginine Rich RNA-Binding Peptides with Picomolar Affinity," J. Am. Chem. Soc., 124, 10966-10967 (2002).

29. 

Jeffrey E. Barrick and Richard W. Roberts.* "Sequence Analysis of an Artificial Family of RNA-Binding Peptides," Protein Science, 11, 2688-2696 (2002).

30. 

Shelley R. Starck and Richard W. Roberts.* "Puromycin Oligonucleotides Reveal Steric Restrictions for Ribosome Entry and Multiple Modes of Translation Inhibition," RNA, 8, 890-903 (2002).

31. 

Rick Baggio, Petra Burgstaller, Steve Hale, Andrew Putney, Meghan Lane, Dasa Lipovsek, Martin C. Wright, Richard W. Roberts, Rihe Liu, Jack W. Szostak and Richard W. Wagner.* "Identification of Epitope-like Consensus Motifs Using mRNA Display," J. Molec. Recog. 15, 126-134 (2002).

32. 

Todd Thorsen, Richard W. Roberts, Frances H. Arnold, and Stephen R. Quake.* "Dynamic Pattern Formation in a Vesicle-Generating Microfluidic Device," Physical Review Letters, 86, 4163-4166 (2001).

33. 

Jeffrey E. Barrick, Terry T. Takahashi, Jinsong Ren, Tianbing Xia and Richard W. Roberts.* "Large Libraries Reveal Diverse Solutions to an RNA Recognition Problem," Proc. Natl. Acad. Sci (USA), 98, 12374-12378 (2001).

34. 

Jeffrey E. Barrick, Terry T. Takahashi, Andrey Balakin, and Richard W. Roberts.* "Selection of RNA-Binding Peptides Using mRNA-Peptide Fusions," Methods 23,287-293 (2001).

35. 

Rihe Liu, Jeffrey Barrick, Jack W. Szostak* and Richard W. Roberts.* "Optimized Synthesis of RNA-Protein Fusions for In Vitro Protein Selection," Methods in Enzymology, 318, 268-293 (2000).

36. 

Richard W. Roberts* and William W. Ja. "In Vitro Selection of Nucleic Acids and Proteins: What Are We Learning?" Current Opinion in Structural Biology, 9, 521-529 (1999).

37. 

Richard W. Roberts.* "Totally In Vitro Protein Selection Using mRNA-Protein Fusions and Ribosome Display," Current Opinion in Chemical Biology, 3, 268-273 (1999).

38. 

Richard W. Roberts and Jack W. Szostak.* "RNA-Peptide Fusions: A Novel System for the In Vitro Selection of Peptides and Proteins," Proc. Natl Acad. Sci. (USA), 94 12297-12302 (1997).

39. 

G. Eric Plum, Richard W. Roberts, and Kenneth J. Breslauer.* "Thermodynamics and Kinetics of Nucleic Acid Association/Dissociation and Folding Processes," in Comprehensive Natural Products Chemistry, 1st ed. (Barton, D. & Nakanishi, K., eds.), Vol. 1. Elsevier, New York (1998).

40. 

Richard W. Roberts* and Donald M. Crothers.* "Prediction of Stability of DNA Triplexes," Proc. Natl Acad. Sci. (USA), 93, 4320-4325 (1996).

41. 

Richard W. Roberts and Donald M. Crothers.* "Kinetic Discrimination in the Formation of Intramolecular Triple Helices," J. Mol. Biol., 260, 135-146 (1996).

42.

Richard W. Roberts and Donald M. Crothers.* "Stability and Properties of Double and Triple Helices: Dramatic Effects of RNA or DNA Backbone Composition," Science, 258, 1463-1466 (1992).

43. 

Richard W. Roberts and Donald M. Crothers.* "Specificity and Stringency in DNA Triplex Formation," Proc. Natl Acad. Sci. (USA), 88, 9397-9401 (1991).

* denotes corresponding author

 

Chemistry Dept., USC College of Letters, Arts & Sciences