Palladium prompted on-demand cysteine chemistry for the synthesis of challenging and uniquely modified proteins

Muhammad Jbara, Shay Laps, Michael Morgan, Guy Kamnesky, Guy Mann, Cynthia Wolberger, Ashraf Brik

Research output: Contribution to journalArticle

Abstract

Organic chemistry allows for the modification and chemical preparation of protein analogues for various studies. The thiolate side chain of the Cys residue has been a key functionality in these ventures. In order to generate complex molecular targets, there is a particular need to incorporate orthogonal protecting groups of the thiolated amino acids to control the directionality of synthesis and modification site. Here, we demonstrate the tuning of palladium chemoselectivity in aqueous medium for on-demand deprotection of several Cys-protecting groups that are useful in protein synthesis and modification. These tools allow the preparation of highly complex analogues as we demonstrate in the synthesis of the copper storage protein and selectively modified peptides with multiple Cys residues. We also report the synthesis of an activity-based probe comprising ubiquitinated histone H2A and its incorporation into nucleosomes and demonstrate its reactivity with deubiquitinating enzyme to generate a covalent nucleosome–enzyme complex.

Original languageEnglish (US)
Article number3154
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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cysteine
Palladium
Cysteine
palladium
chemistry
proteins
synthesis
Organic Chemistry
analogs
protein synthesis
organic chemistry
preparation
Proteins
Nucleosomes
Histones
peptides
amino acids
enzymes
Copper
reactivity

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Palladium prompted on-demand cysteine chemistry for the synthesis of challenging and uniquely modified proteins. / Jbara, Muhammad; Laps, Shay; Morgan, Michael; Kamnesky, Guy; Mann, Guy; Wolberger, Cynthia; Brik, Ashraf.

In: Nature Communications, Vol. 9, No. 1, 3154, 01.12.2018.

Research output: Contribution to journalArticle

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