Kirchgäßner, S., Braun, M.B., Bartlick, N. et al. (5 more authors) (2023) Synthesis, biochemical characterization, and genetic encoding of a 1,2,4‐triazole amino acid as an acetyllysine mimic for bromodomains of the BET family. Angewandte Chemie International Edition, 62 (12). e202215460. ISSN 1433-7851
Abstract
Lysine acetylation is a charge-neutralizing post-translational modification of proteins bound by bromodomains (Brds). A 1,2,4-triazole amino acid (ApmTri) was established as acetyllysine (Kac) mimic recruiting Brds of the BET family in contrast to glutamine commonly used for simulating this modification. Optimization of triazole substituents and side chain spacing allowed BET Brd recruitment to ApmTri-containing peptides with affinities similar to native substrates. Crystal structures of ApmTri-containing peptides in complex with two BET Brds revealed the binding mode which mirrored that of Kac ligands. ApmTri was genetically encoded and recombinant ApmTri-containing proteins co-enriched BRD3(2) from cellular lysates. This interaction was blocked by BET inhibitor JQ1. With genetically encoded ApmTri, biochemistry is now provided with a stable Kac mimic reflecting charge neutralization and Brd recruitment, allowing new investigations into BET proteins in vitro and in vivo.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | chemical biology; protein modification; lysine acetylation; bromodomain; genetic code expansion |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 14 Feb 2023 11:59 |
Last Modified: | 27 Sep 2024 15:00 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/anie.202215460 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:196360 |