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 and Ashraf Brik ()
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Muhammad Jbara: Technion-Israel Institute of Technology
Shay Laps: Technion-Israel Institute of Technology
Michael Morgan: Johns Hopkins University School of Medicine
Guy Kamnesky: Technion-Israel Institute of Technology
Guy Mann: Technion-Israel Institute of Technology
Cynthia Wolberger: Johns Hopkins University School of Medicine
Ashraf Brik: Technion-Israel Institute of Technology

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05628-0

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