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Selenomethionine as an expressible handle for bioconjugations

Flood, Dillon T. and Hintzen, Jordi C. J. and Knouse, Kyle W. and Hill, David E. and Lu, Chenxi and Cistrone, Philip A. and Chen, Jason S. and Otomo, Takanori and Dawson, Philip E. (2021) Selenomethionine as an expressible handle for bioconjugations. Proceedings of the National Academy of Sciences of the United States of America, 118 (8). Art. No. e2005164118. ISSN 0027-8424. PMCID PMC7923357.

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Site-selective chemical bioconjugation reactions are enabling tools for the chemical biologist. Guided by a careful study of the selenomethionine (SeM) benzylation, we have refined the reaction to meet the requirements of practical protein bioconjugation. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, is selectively labile to glutathione, and embodies a broadly tunable cleavage profile. Specifically, a 4-bromomethylphenylacetyl (BrMePAA) linker has been applied for efficient conjugation of complex organic molecules to SeM-containing proteins. This expansion of the bioconjugation toolkit has broad potential in the development of chemically enhanced proteins.

Item Type:Article
Related URLs:
URLURL TypeDescription Information
Flood, Dillon T.0000-0002-6600-0287
Hintzen, Jordi C. J.0000-0002-4621-0711
Knouse, Kyle W.0000-0001-9688-0513
Hill, David E.0000-0002-7326-2509
Lu, Chenxi0000-0001-7586-2199
Otomo, Takanori0000-0003-3589-238X
Dawson, Philip E.0000-0002-2538-603X
Additional Information:© 2021 National Academy of Sciences. Published under the PNAS license. Edited by David Baker, University of Washington, Seattle, WA, and approved January 4, 2021 (received for review March 24, 2020). Financial support for this work was from NIH (GM-132787 to P.E.D. and GM092740 to T.O.). D.T.F. was supported by the National Center for Advancing Translational Sciences, NIH, through Grant UL1 TR002551 and linked award TL1 TR002551. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We are grateful to Dr. Dee-Hua Huang and Dr. Laura Pasternack (Scripps Research) for assistance with nuclear magnetic resonance spectroscopy. Data Availability: All study data are included in this article and/or SI Appendix. Author contributions: D.T.F., D.E.H., and P.E.D. designed research; D.T.F., J.C.J.H., K.W.K., D.E.H., C.L., P.A.C., and T.O. performed research; D.T.F. and J.S.C. contributed new reagents/analytic tools; D.T.F., J.C.J.H., D.E.H., T.O., and P.E.D. analyzed data; and D.T.F. and P.E.D. wrote the paper. The authors declare no competing interest. This article is a PNAS Direct Submission. This article contains supporting information online at
Funding AgencyGrant Number
NIHUL1 TR002551
NIHTL1 TR002551
Subject Keywords:bioconjugation; selenomethionine; protein chemistry
Issue or Number:8
PubMed Central ID:PMC7923357
Record Number:CaltechAUTHORS:20210219-111631143
Persistent URL:
Official Citation:Selenomethionine as an expressible handle for bioconjugations. Dillon T. Flood, Jordi C. J. Hintzen, Kyle W. Knouse, David E. Hill, Chenxi Lu, Philip A. Cistrone, Jason S. Chen, Takanori Otomo, Philip. E. Dawson. Proceedings of the National Academy of Sciences Feb 2021, 118 (8) e2005164118; DOI: 10.1073/pnas.2005164118
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108120
Deposited By: Tony Diaz
Deposited On:19 Feb 2021 19:34
Last Modified:21 Apr 2021 18:53

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