5IGM

Crystal structure of the bromodomain of human BRD9 in complex with bromosporine (BSP)

5IGM の概要

• エントリーDOI: 10.2210/pdb5igm/pdb
• 分子名称: Bromodomain-containing protein 9, Bromosporine (3 entities in total)
• 機能のキーワード: chromatin remodeling, transcription, structural genomics, structural genomics consortium, sgc
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29308.41

構造登録者

Tallant, C.,Filippakopoulos, P.,Picaud, S.,Nunez-Alonso, G.,von Delft, F.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2016-02-28, 公開日: 2016-10-19, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.6 Å)