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Isoxazole-Derived Amino Acids are Bromodomain-Binding Acetyl-Lysine Mimics: Incorporation into Histone H4 Peptides and Histone H3.

Published version
Peer-reviewed

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Type

Article

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Authors

Sekirnik Née Measures, Angelina R 
Hewings, David S 
Theodoulou, Natalie H 
Jursins, Lukass 
Lewendon, Katie R 

Abstract

A range of isoxazole-containing amino acids was synthesized that displaced acetyl-lysine-containing peptides from the BAZ2A, BRD4(1), and BRD9 bromodomains. Three of these amino acids were incorporated into a histone H4-mimicking peptide and their affinity for BRD4(1) was assessed. Affinities of the isoxazole-containing peptides are comparable to those of a hyperacetylated histone H4-mimicking cognate peptide, and demonstrated a dependence on the position at which the unnatural residue was incorporated. An isoxazole-based alkylating agent was developed to selectively alkylate cysteine residues in situ. Selective monoalkylation of a histone H4-mimicking peptide, containing a lysine to cysteine residue substitution (K12C), resulted in acetyl-lysine mimic incorporation, with high affinity for the BRD4 bromodomain. The same technology was used to alkylate a K18C mutant of histone H3.

Description

Keywords

alkylation, amino acids, bromodomain, electrostatic interactions, mass spectrometry, protein modifications

Journal Title

Angew Chem Int Ed Engl

Conference Name

Journal ISSN

1433-7851
1521-3773

Volume Title

55

Publisher

Wiley
Sponsorship
Pfizer Neusentis for studentship support