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Dengler, A.S. ; Lunglmeir, L. ; Brandl, M.J.* ; Alderson, T.R.

Bromodomain dimers: A case study of BRD4 and family-wide AlphaFold predictions.

Struct. Dyn.-US 13:034702 (2026)
Publ. Version/Full Text Research data DOI
Open Access Gold
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Bromodomains are conserved acetyl-lysine reader domains that play a central role in the assembly of transcriptional regulatory complexes. While generally presumed to function as monomers, bromodomain homo-dimers have been identified, and several bromodomain-containing proteins have been linked to biomolecular condensates, where locally elevated concentrations may promote dimerization. Here, we investigated bromodomain dimerization with an integrated approach that combines structural and biophysical measurements with AlphaFold-based predictions across the bromodomain family. Using the second bromodomain (BD2) of BRD4 as a model system, we characterized the thermodynamics and kinetics of its monomer-dimer equilibrium by two-dimensional nuclear magnetic resonance (NMR) lineshape analysis and CPMG relaxation dispersion. We found that the BRD4BD2 dimer forms transiently with a dissociation constant near 400 μM and a lifetime near 1 ms. Using our NMR-derived restraints, we performed data-driven docking to generate models of the BRD4BD2 dimer. To assess dimerization propensity across the wider bromodomain family, we leveraged AlphaFold-Multimer and AlphaFold3 to systematically predict homo-dimeric models for all human bromodomains. We identified several predicted dimer architectures, with 15 bromodomain dimers that have higher interface-confidence scores than BRD4BD2. Overall, our results suggest that weak and reversible dimerization may be more widespread among bromodomains, where it could contribute to function in dynamic transcriptional assemblies.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Relaxation Dispersion Nmr; Small-angle Scattering; Time-scale Dynamics; N-15 Relaxation; Multidimensional Nmr; Macromolecular Assemblies; Protein Association; Chemical-exchange; Backbone Dynamics; Structural Basis
ISSN (print) / ISBN 2329-7778
e-ISSN 2329-7778
Journal Structural Dynamics
Quellenangaben Volume: 13, Issue: 3, Pages: , Article Number: 034702 Supplement: ,
Publisher American Crystallographic Association
Publishing Place 1305 Walt Whitman Rd, Ste 300, Melville, Ny 11747-4501 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
Institute of Computational Biology (ICB)
Grants EGI-ACE
National Institute of General Medical Sciences
EOSC-Life
Helmholtz Association
FP7 Joint Research Centre
Yes, funding has been received from NIH