Synthesis and Macrodomain Binding of Gln-carba-ADPr-peptide

Chembiochem. 2024 Mar 5:e202300865. doi: 10.1002/cbic.202300865. Online ahead of print.ABSTRACTMono-ADP-ribosylation is a dynamic post-translational modification (PTM) with important roles in cell signalling. This modification occurs on a wide variety of amino acids, and one of the canonical modification sites within proteins is the side chain of glutamic acid. Given the transient nature of this modification (acylal linkage) and the high sensitivity of ADP-ribosylated glutamic acid, stabilized isosteres are required for structural and biochemical studies. Here, we report the synthesis of a mimic of ADP-ribosylated peptide derived from histone H2B that contains carba-ADP-ribosylated glutamine as a potential mimic for Glu-ADPr. We synthesized a cyclopentitol-ribofuranosyl derivative of 5'-phosphoribosylated Fmoc-glutamine and used this in the solid-phase synthesis of the carba-ADPr-peptide mimicking the ADP-ribosylated N-terminal tail of histone H2B. Binding studies with isothermal calorimetry demonstrate that the macrodomains of human MacroD2 and TARG1 bind to carba-ADPr-peptide in the same way as ADPr-peptides containing the native ADP-riboside moiety connected to the side chain of glutamine in the same peptide sequence.PMID:38442082 | DOI:10.1002/cbic.202300865

Source: Chembiochem - March 5, 2024 Category: Biochemistry Authors: Sande B Engelsma Aurelio Pio Nardozza Pieter de Saint Aulaire Herman S Overkleeft Gijsbert A van der Marel Andreas G Ladurner Dmitri Filippov Source Type: research