5IGK

Crystal structure of the first bromodomain of human BRD4 in complex with bromosporine (BSP)

Summary for 5IGK

• Entry DOI: 10.2210/pdb5igk/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, Bromosporine, ... (4 entities in total)
• Functional Keywords: transcription, post translational modifications, bet family, structural genomics, structural genomics consortium, sgc
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15565.89

Authors

Filippakopoulos, P.,Picaud, S.,Felletar, I.,von Delft, F.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2016-02-28, release date: 2016-10-19, Last modification date: 2024-01-10)

Primary citation

Picaud, S.,Leonards, K.,Lambert, J.P.,Dovey, O.,Wells, C.,Fedorov, O.,Monteiro, O.,Fujisawa, T.,Wang, C.Y.,Lingard, H.,Tallant, C.,Nikbin, N.,Guetzoyan, L.,Ingham, R.,Ley, S.V.,Brennan, P.,Muller, S.,Samsonova, A.,Gingras, A.C.,Schwaller, J.,Vassiliou, G.,Knapp, S.,Filippakopoulos, P.
Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia.
Sci Adv, 2:e1600760-e1600760, 2016

PubMed Abstract: Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.

PubMed: 27757418
DOI: 10.1126/sciadv.1600760

Experimental method

X-RAY DIFFRACTION (1.7 Å)