Phosphorylation-dependent BRD4 dimerization and implications for therapeutic inhibition of BET family proteins

Francesca Malvezzi; Christopher J. Stubbs; Thomas A. Jowitt; Ian L. Dale; Xieyang Guo; Jon P. DeGnore; Gianluca Degliesposti; J. Mark Skehel; Andrew J. Bannister; Mark S. McAlister

doi:10.1038/s42003-021-02750-6

Communications Biology (Nov 2021)

Phosphorylation-dependent BRD4 dimerization and implications for therapeutic inhibition of BET family proteins

Francesca Malvezzi,
Christopher J. Stubbs,
Thomas A. Jowitt,
Ian L. Dale,
Xieyang Guo,
Jon P. DeGnore,
Gianluca Degliesposti,
J. Mark Skehel,
Andrew J. Bannister,
Mark S. McAlister

Affiliations

Francesca Malvezzi: Structure, Biophysics and Fragment-Based Lead Generation, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Christopher J. Stubbs: Structure, Biophysics and Fragment-Based Lead Generation, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Thomas A. Jowitt: Wellcome Trust Centre for Cell-Matrix Research, University of Manchester
Ian L. Dale: Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Xieyang Guo: Structure, Biophysics and Fragment-Based Lead Generation, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Jon P. DeGnore: Mechanistic Biology & Profiling, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca
Gianluca Degliesposti: Biological Mass Spectrometry and Proteomics, MRC Laboratory of Molecular Biology, Francis Crick Avenue
J. Mark Skehel: Biological Mass Spectrometry and Proteomics, MRC Laboratory of Molecular Biology, Francis Crick Avenue
Andrew J. Bannister: The Gurdon Institute and Department of Pathology, University of Cambridge
Mark S. McAlister: Structure, Biophysics and Fragment-Based Lead Generation, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca

DOI: https://doi.org/10.1038/s42003-021-02750-6
Journal volume & issue: Vol. 4, no. 1
pp. 1 – 13

Abstract

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Malvezzi et al. discuss the impact of BRD4 phosphorylation on the formation of dimers and identify the key residues necessary for this dimerization. They also discuss the differential role of monovalent and bivalents bromodomain inhibitors regarding the interaction with these dimers and suggest a new model of BRD4 binding to chromatin.

Published in Communications Biology

ISSN: 2399-3642 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science: Biology (General)
Website: https://www.nature.com/commsbio/

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