Technion researchers; Muhammad Jbara, Shay Laps, Dr. Guy Kamnesky & Guy Mann from the lab of Prof. Ashraf Brik at the Schulich Faculty of Chemistry, in collaboration with Prof. Cynthia Wolberger from Johns Hopkins University, School of Medicine reported on tuning palladium chemoselectivity for the synthesis of challenging and uniquely modified proteins, as very recently was published in Nature Communications.
Organic chemistry has revolutionized the field of protein science by contributing efficient synthetic tools to prepare various protein analogues, such as proteins labeled with fluorophores, D-amino acids and posttranslational modifications (PTMs). These analogues have been utilized in various biochemical, structural and functional 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. In this work, the group demonstrated 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 allowed the preparation of highly complex analogues as demonstrated in the synthesis of the copper storage protein and selectively modified peptides with multiple Cys residues. The group also reported the synthesis of an activity-based probe comprising ubiquitinated histone H2A and its incorporation into nucleosomes and demonstrated its reactivity with deubiquitinating enzyme to generate a covalent nucleosome–enzyme complex.
This study was partially supported by the United States-Israel Binational Science Foundation, BSF 2014029 (A.B. and C.W.).