Bromodomain Interactions with Acetylated Histone 4 Peptides in the BRD4 Tandem Domain: Effects on Domain Dynamics and Internal Flexibility.


Journal

Biochemistry
ISSN: 1520-4995
Titre abrégé: Biochemistry
Pays: United States
ID NLM: 0370623

Informations de publication

Date de publication:
01 11 2022
Historique:
pubmed: 11 10 2022
medline: 3 11 2022
entrez: 10 10 2022
Statut: ppublish

Résumé

The bromodomain and extra-terminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Like other BET proteins, BRD4 contains two bromodomains, BD1 and BD2, that can interact cooperatively with target proteins and designed ligands, with important implications for drug discovery. Here, we used nuclear magnetic resonance (NMR) spectroscopy to study the dynamics and interactions of the isolated bromodomains, as well as the tandem construct including both domains and the intervening linker, and investigated the effects of binding a tetra-acetylated peptide corresponding to the tail of histone 4. The peptide affinity is lower for both domains in the tandem construct than for the isolated domains. Using

Identifiants

pubmed: 36215732
doi: 10.1021/acs.biochem.2c00226
pmc: PMC9631989
doi:

Substances chimiques

Histones 0
Nuclear Proteins 0
Transcription Factors 0
Peptides 0
Cell Cycle Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2303-2318

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Auteurs

Sven Wernersson (S)

Biophysical Chemistry, Center for Molecular Protein Science, Department of Chemistry, Lund University, SE-221 00Lund, Sweden.

Romel Bobby (R)

Mechanistic and Structural Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, CambridgeCB4 0WG, U.K.

Liz Flavell (L)

Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge Science Park, CambridgeCB4 0WG, U.K.

Alexander G Milbradt (AG)

Mechanistic and Structural Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, CambridgeCB4 0WG, U.K.

Geoffrey A Holdgate (GA)

Mechanistic and Structural Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, CambridgeCB4 0WG, U.K.

Kevin J Embrey (KJ)

Mechanistic and Structural Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, CambridgeCB4 0WG, U.K.

Mikael Akke (M)

Biophysical Chemistry, Center for Molecular Protein Science, Department of Chemistry, Lund University, SE-221 00Lund, Sweden.

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Classifications MeSH