Genetic Incorporation of a Reactive Isothiocyanate Group into Proteins

Xuan, Weimin; Li, Jack; Luo, Xiaozhou; Schultz, Peter G.

doi:10.1002/anie.201604891

Title: Genetic Incorporation of a Reactive Isothiocyanate Group into Proteins

Abstract

Abstract Methods for the site‐specific modification of proteins are useful for introducing biological probes into proteins and engineering proteins with novel activities. Herein, we genetically encode a novel noncanonical amino acid (ncAA) that contains an aryl isothiocyanate group which can form stable thiourea crosslinks with amines under mild conditions. We show that this ncAA (pNCSF) allows the selective conjugation of proteins to amine‐containing molecular probes through formation of a thiourea bridge. pNCSF was also used to replace a native salt bridge in myoglobin with an intramolecular crosslink to a proximal Lys residue, leading to increased thermal stability. Finally, we show that pNCSF can form stable intermolecular crosslinks between two interacting proteins.

Authors:

Xuan, Weimin ^[1]; Li, Jack ^[1]; Luo, Xiaozhou ^[1]; Schultz, Peter G. ^[1]

Department of Chemistry The Scripps Research Institute 10550 N. Torrey Pines Road La Jolla CA 92037 USA

Publication Date:: Fri Jul 15 00:00:00 EDT 2016

Sponsoring Org.:: USDOE

OSTI Identifier:: 1401865

Grant/Contract Number:: SC0011787

Resource Type:: Publisher's Accepted Manuscript

Journal Name:: Angewandte Chemie (International Edition)

Additional Journal Information:: Journal Name: Angewandte Chemie (International Edition) Journal Volume: 55 Journal Issue: 34; Journal ID: ISSN 1433-7851

Publisher:: Wiley Blackwell (John Wiley & Sons)

Country of Publication:: Germany

Language:: English

Citation Formats


                    Xuan, Weimin, Li, Jack, Luo, Xiaozhou, and Schultz, Peter G. Genetic Incorporation of a Reactive Isothiocyanate Group into Proteins.  Germany: N. p., 2016. 
Web.  doi:10.1002/anie.201604891.

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                    Xuan, Weimin, Li, Jack, Luo, Xiaozhou, & Schultz, Peter G. Genetic Incorporation of a Reactive Isothiocyanate Group into Proteins.  Germany.  https://doi.org/10.1002/anie.201604891

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                    Xuan, Weimin, Li, Jack, Luo, Xiaozhou, and Schultz, Peter G. Fri .  
"Genetic Incorporation of a Reactive Isothiocyanate Group into Proteins".  Germany.  https://doi.org/10.1002/anie.201604891.

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@article{osti_1401865,

  title        = {Genetic Incorporation of a Reactive Isothiocyanate Group into Proteins},

  author       = {Xuan, Weimin and Li, Jack and Luo, Xiaozhou and Schultz, Peter G.},

  abstractNote = {Abstract Methods for the site‐specific modification of proteins are useful for introducing biological probes into proteins and engineering proteins with novel activities. Herein, we genetically encode a novel noncanonical amino acid (ncAA) that contains an aryl isothiocyanate group which can form stable thiourea crosslinks with amines under mild conditions. We show that this ncAA (pNCSF) allows the selective conjugation of proteins to amine‐containing molecular probes through formation of a thiourea bridge. pNCSF was also used to replace a native salt bridge in myoglobin with an intramolecular crosslink to a proximal Lys residue, leading to increased thermal stability. Finally, we show that pNCSF can form stable intermolecular crosslinks between two interacting proteins.},

  doi          = {10.1002/anie.201604891},

  journal      = {Angewandte Chemie (International Edition)},

  number       = 34,

  volume       = 55,

  place        = {Germany},

  year         = {Fri Jul 15 00:00:00 EDT 2016},

  month        = {Fri Jul 15 00:00:00 EDT 2016}

}

Copy to clipboard

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Title: Genetic Incorporation of a Reactive Isothiocyanate Group into Proteins

Abstract

Citation Formats

Proximity-Enabled Protein Crosslinking through Genetically Encoding Haloalkane Unnatural Amino Acids journal, January 2014

Genetic Encoding and Labeling of Aliphatic Azides and Alkynes in Recombinant Proteins via a Pyrrolysyl-tRNA Synthetase/tRNA CUA Pair and Click Chemistry journal, July 2009

Addition of the keto functional group to the genetic code of Escherichia coli journal, December 2002

Site-selective protein-modification chemistry for basic biology and drug development journal, November 2015

Redirecting lipoic acid ligase for cell surface protein labeling with small-molecule probes journal, December 2007

In vivo incorporation of an alkyne into proteins in Escherichia coli journal, March 2005

Homogeneously modified immunoglobulin domains for therapeutic application journal, October 2015

Labeling Proteins with Small Molecules by Site-Specific Posttranslational Modification journal, June 2004

A Genetically Encoded Boronate-Containing Amino Acid journal, October 2008

Cysteinselektive Reaktionen zur Konjugation von Antikörpern journal, July 2014

Methotrexate Conjugates: A Molecular In Vivo Protein Tag journal, March 2004

A Genetically Encoded Diazirine Photocrosslinker inEscherichia coli journal, December 2007

A Genetically Encoded Acrylamide Functionality journal, June 2013

Therapeutic Applications of an Expanded Genetic Code journal, July 2014

Site-Specific Incorporation of Photo-Cross-Linker and Bioorthogonal Amino Acids into Enteric Bacterial Pathogens journal, December 2011

Adding an unnatural covalent bond to proteins through proximity-enhanced bioreactivity journal, August 2013

Sortagging: a versatile method for protein labeling journal, September 2007

The Site-Specific Installation of Methyl-Lysine Analogs into Recombinant Histones journal, March 2007

Inteins: nature's gift to protein chemists journal, January 2014

Structural basis for recognition by an in vitro evolved affibody journal, February 2003

Adding New Chemistries to the Genetic Code journal, June 2010

Proximity-Enabled Protein Crosslinking through Genetically Encoding Haloalkane Unnatural Amino Acids journal, January 2014

Addition of p-Azido-L-phenylalanine to the Genetic Code of Escherichia coli journal, July 2002

A Genetically Encoded Boronate-Containing Amino Acid journal, October 2008

Exploring the potential impact of an expanded genetic code on protein function journal, May 2015

Introducing genetically encoded aldehydes into proteins journal, April 2007

Method for Determination of the Amino Acid Sequence in Peptides. journal, January 1950

Cysteine-Selective Reactions for Antibody Conjugation journal, July 2014

π-Clamp-mediated cysteine conjugation journal, December 2015

A Genetically Encoded aza-Michael Acceptor for Covalent Cross-Linking of Protein–Receptor Complexes journal, May 2014

Expanding the chemical toolbox for the synthesis of large and uniquely modified proteins journal, April 2016

Addition of a photocrosslinking amino acid to the genetic code of Escherichia coli journal, August 2002

A general method for the covalent labeling of fusion proteins with small molecules in vivo journal, December 2002

An Evolved Aminoacyl-tRNA Synthetase with Atypical Polysubstrate Specificity, journal, March 2011

Methotrexate Conjugates: A Molecular In Vivo Protein Tag journal, March 2004

Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli journal, June 2009

Gleaning Unexpected Fruits from Hard-Won Synthetases: Probing Principles of Permissivity in Non-canonical Amino Acid-tRNA Synthetases journal, July 2014

Proximity-Enabled Protein Crosslinking through Genetically Encoding Haloalkane Unnatural Amino Acids
journal, January 2014

Genetic Encoding and Labeling of Aliphatic Azides and Alkynes in Recombinant Proteins via a Pyrrolysyl-tRNA Synthetase/tRNA _CUA Pair and Click Chemistry
journal, July 2009

Addition of the keto functional group to the genetic code of Escherichia coli
journal, December 2002

Site-selective protein-modification chemistry for basic biology and drug development
journal, November 2015

Redirecting lipoic acid ligase for cell surface protein labeling with small-molecule probes
journal, December 2007

In vivo incorporation of an alkyne into proteins in Escherichia coli
journal, March 2005

Homogeneously modified immunoglobulin domains for therapeutic application
journal, October 2015

Labeling Proteins with Small Molecules by Site-Specific Posttranslational Modification
journal, June 2004

A Genetically Encoded Boronate-Containing Amino Acid
journal, October 2008

Cysteinselektive Reaktionen zur Konjugation von Antikörpern
journal, July 2014

Methotrexate Conjugates: A Molecular In Vivo Protein Tag
journal, March 2004

A Genetically Encoded Diazirine Photocrosslinker inEscherichia coli
journal, December 2007

A Genetically Encoded Acrylamide Functionality
journal, June 2013

Therapeutic Applications of an Expanded Genetic Code
journal, July 2014

Site-Specific Incorporation of Photo-Cross-Linker and Bioorthogonal Amino Acids into Enteric Bacterial Pathogens
journal, December 2011

Adding an unnatural covalent bond to proteins through proximity-enhanced bioreactivity
journal, August 2013

Sortagging: a versatile method for protein labeling
journal, September 2007

The Site-Specific Installation of Methyl-Lysine Analogs into Recombinant Histones
journal, March 2007

Inteins: nature's gift to protein chemists
journal, January 2014

Structural basis for recognition by an in vitro evolved affibody
journal, February 2003

Adding New Chemistries to the Genetic Code
journal, June 2010

Proximity-Enabled Protein Crosslinking through Genetically Encoding Haloalkane Unnatural Amino Acids
journal, January 2014

Addition of p-Azido-L-phenylalanine to the Genetic Code of Escherichia coli
journal, July 2002

A Genetically Encoded Boronate-Containing Amino Acid
journal, October 2008

Exploring the potential impact of an expanded genetic code on protein function
journal, May 2015

Introducing genetically encoded aldehydes into proteins
journal, April 2007

Method for Determination of the Amino Acid Sequence in Peptides.
journal, January 1950

Cysteine-Selective Reactions for Antibody Conjugation
journal, July 2014

π-Clamp-mediated cysteine conjugation
journal, December 2015

A Genetically Encoded aza-Michael Acceptor for Covalent Cross-Linking of Protein–Receptor Complexes
journal, May 2014

Expanding the chemical toolbox for the synthesis of large and uniquely modified proteins
journal, April 2016

Addition of a photocrosslinking amino acid to the genetic code of Escherichia coli
journal, August 2002

A general method for the covalent labeling of fusion proteins with small molecules in vivo
journal, December 2002

An Evolved Aminoacyl-tRNA Synthetase with Atypical Polysubstrate Specificity,
journal, March 2011

Methotrexate Conjugates: A Molecular In Vivo Protein Tag
journal, March 2004

Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli
journal, June 2009

Gleaning Unexpected Fruits from Hard-Won Synthetases: Probing Principles of Permissivity in Non-canonical Amino Acid-tRNA Synthetases
journal, July 2014