Scripps Research Joint Appointments

Department of Chemistry
Faculty, Graduate Program

Research Focus

Development & Utilization of Methods to Incorporate Unnatural Chemical Groups into Proteins

We have developed a chemical approach for the production of the large polypeptide chains that comprise protein molecules, enabling us to change the structure of a protein in ways impossible by natural means. We use solid phase peptide synthesis to generate peptides up to ~50 amino acids in length and then assemble them using chemoselective reactions to make proteins up to ~150 amino acids in length. This—chemical ligation—approach greatly facilitates the synthesis of proteins of moderate size and has opened the world of proteins to the synthetic tools of organic chemistry. Chemical ligation can be extended to biologically expressed proteins enabling the semisynthesis of proteins of unlimited size that contain fluorophores or cross-linking agents at defined positions. Our goal is to introduce non-coded amino acids and other chemical groups into proteins to better understand the molecular basis of protein function.

Education

Ph.D., Macromolecular and Cellular Structure and Chemistry, Scripps Research, 1996
A.B., Chemistry, Washington University in St. Louis, 1992

Professional Experience

2016-present, Professor, Department of Chemistry, Scripps Research

2017-present, Dean of Graduate and Postdoctoral Studies, Skaggs Graduate School of Chemical and Biological Science, Scripps Research

2012-2017, Associate Dean of Graduate and Postdoctoral Studies, Scripps Research

2010-2016, Associate Professor, Department of Chemistry, Scripps Research

2005-2010, Associate Professor, Department of Cell Biology, Scripps Research

1997-2005, Assistant Professor, Department of Cell Biology, The Skaggs Institute for Chemical Biology, Scripps Research

1996-1997, Postdoctoral Scholar with Drs. Harry B. Gray and Thomas J. Meade, Department of Chemistry, California Institute of Technology

Awards & Professional Activities

•Alfred P. Sloan Fellow, 1999-2001
•Vincent du Vigneaud Award, 2010
•Gold Medal of the Max Bergmann Kreis, 2011
•Chairman, American Peptide Symposium, 2011
•Co-Chairman, Gordon Research Conference, 2016
•Elected President, American Peptide Society, 2013-2018
•Leonidas Zervas Award, 2014
•Akabori Memorial Award, Japanese Peptide Society, 2020

•100 Invited lectures
•6 Scientific Advisory Boards
•4 Journal Editorial Boards
•>190 Peer Reviewed Publications
•21,899 citations
•>35 graduate and postdoctoral students

Selected References

Flood DT, Hintzen JCJ, Knouse KW, Hill DE, Lu C, Cistrone PA, Chen JS, Otomo T, Dawson PE. Selenomethionine as an expressible handle for bioconjugations. Proc Natl Acad Sci USA 2021, 118(8) e2005164118. 10.1073/pnas.2005164118

Flood DT, Knouse KW, Vantourout JC, Kitamura S, Sanchez BB, Sturgell EJ, Chen JS, Wolan DW, Baran PS, Dawson PE. Synthetic Elaboration of Native DNA by RASS (SENDR). ACS Cent Sci 2020, 6, 1789-99. 10.1021/acscentsci.0c00680

Flood DT, Hintzen JCJ, Bird MJ, Cistrone PA, Chen JS, Dawson PE. Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in NCL. Angew Chem Int Ed Engl. 2018, 57, 11634-9. 10.1002/anie.201805191

Flood DT, Yan NL, Dawson PE. Post-Translational Backbone Engineering through Selenomethionine-Mediated Incorporation of Freidinger Lactams. Angew Chem Int Ed Engl. 2018, Epub ahead of print. 10.1002/anie.201804885

Silvestri AP, Cistrone PA, Dawson PE. Adapting the Glaser Reaction for Bioconjugation: Robust Access to Structurally Simple, Rigid Linkers. Angew Chem Int Ed 2017, 56(35), 10438-42. 10.1002/anie.201705065

Reichart TM, Baksh MM, Rhee JK, Fiedler JD, Sligar SG, Finn MG, Zwick MB, Dawson PE. Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding. Angew Chem Int Ed. 2016, 55(8), 2688-92. doi: 10.1002/anie.201508421

Blanco-Canosa JB, Nardone B, Albericio F, Dawson PE. Chemical Protein Synthesis Using a Second-Generation N-Acylurea Linker for the Preparation of Peptide-Thioester Precursors. Journal of the American Chemical Society 2015, 137(22):7197-209. doi: 10.1021/jacs.5b03504

Assem N, Ferreira DJ, Wolan DW, Dawson PE. Acetone-Linked Peptides: A Convergent Approach for Peptide Macrocyclization and Labeling. Angew Chem Int Ed. 2015, 54(30), 8665-8. doi: 10.1002/anie.201502607

Metanis N, Keinan E, Dawson PE. Traceless ligation of cysteine peptides using selective deselenization. Angew Chem Int Ed 2010, 49(39), 7049-53. doi:10.1002/anie.201001900

Vanacore R, Ham AJL, Voehler M, Sanders CR, Conrads TP, Veenstra TD, Sharpless KB, Dawson PE, Hudson BG. A sulfilimine bond identified in collagen IV. Science 2009, 325(5945), 1230-34. PMC2876822. 10.1126/science.1176811

Blanco-Canosa JB, Dawson PE. An efficient Fmoc-SPPS approach for the generation of thioester peptide precursors for use in native chemical ligation. Angew Chem Int Ed 2008, 47(36), 6851-55. doi:10.1002/anie.200705471

Medintz IL, Clapp AR, Brunel FM, Tiefenbrunn T, Uyeda HT, Chang EL, Deschamps JR, Dawson PE, Mattoussi H. Proteolytic activity monitored by fluorescence resonance energy transfer through quantum-dot-peptide conjugates. Nature Materials 2006, 5(7), 581-89. 10.1038/nmat1676

Dirksen A, Hackeng TM, Dawson PE. Nucleophilic catalysis of oxime ligation. Angew Chem Int Ed Engl. 2006, 45(45), 7581-84. 10.1002/anie.200602877

Links

The Skaggs Institute Scientific Report