6G0P

Crystal Structure of the first bromodomain of human BRD4 in complex with an acetylated E2F1 peptide (K117ac/K120ac)

Summary for 6G0P

• Entry DOI: 10.2210/pdb6g0p/pdb
• Descriptor: Bromodomain-containing protein 4, Transcription factor E2F1, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: bromodomain, transcription, complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 17004.47

Authors

Filippakopoulos, P.,Picaud, S.,Krojer, T.,Sorrell, F.,Pike, A.C.W.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C. (deposition date: 2018-03-19, release date: 2018-11-28, Last modification date: 2024-01-17)

Primary citation

Lambert, J.P.,Picaud, S.,Fujisawa, T.,Hou, H.,Savitsky, P.,Uuskula-Reimand, L.,Gupta, G.D.,Abdouni, H.,Lin, Z.Y.,Tucholska, M.,Knight, J.D.R.,Gonzalez-Badillo, B.,St-Denis, N.,Newman, J.A.,Stucki, M.,Pelletier, L.,Bandeira, N.,Wilson, M.D.,Filippakopoulos, P.,Gingras, A.C.
Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.
Mol. Cell, 73:621-638.e17, 2019

PubMed Abstract: Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4, and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behavior for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain binding motifs mediate acetylation-independent interactions. Last, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1.

PubMed: 30554943
DOI: 10.1016/j.molcel.2018.11.006

Experimental method

X-RAY DIFFRACTION (1.3 Å)