Synthesis, Biochemical Characterization, and Genetic Encoding of a 1,2,4-Triazole Amino Acid as an Acetyllysine Mimic for Bromodomains of the BET Family

被引：6
作者：
Kirchgaessner, Soeren [1 ]
Braun, Michael B. [1 ]
Bartlick, Natascha [1 ]
Koc, Cengiz [1 ,2 ]
Reinkemeier, Christopher D. [3 ,4 ,5 ]
Lemke, Edward A. [3 ,4 ]
Stehle, Thilo [1 ]
Schwarzer, Dirk [1 ]
机构：
[1] Univ Tubingen, Interfak Inst Biochem, Auf Der Morgenstelle 34, D-72076 Tubingen, Germany
[2] Univ Sheffield, Med Sch, Dept Infect Immun & Cardiovasc Dis, Beech Hill Rd, Sheffield S10 2RX, England
[3] Johannes Gutenberg Univ Mainz, Bioctr, D-55128 Mainz, Germany
[4] Inst Mol Biol Mainz, D-55128 Mainz, Germany
[5] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn Basel, Mattenstr 26, CH-4058 Basel, Switzerland
来源：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2023年 / 62卷 / 12期
关键词：
Bromodomain; Chemical Biology; Genetic Code Expansion; Lysine Acetylation; Protein Modification; TRANSFER-RNA SYNTHETASE; CODE EXPANSION; LYSINE; ACETYLATION; ROLES; TRANSCRIPTION; DEACETYLASES; EPIGENETICS; METABOLISM; COMPLEXES;
D O I：
10.1002/anie.202215460
中图分类号：
O6 [化学];
学科分类号：
0703 ;
摘要：
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.
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页数：7
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