5LUU

Structure of the first bromodomain of BRD4 with a pyrazolo[4,3-c]pyridin fragment

5LUU の概要

• エントリーDOI: 10.2210/pdb5luu/pdb
• 分子名称: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 1-(3-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)propan-1-one, ... (4 entities in total)
• 機能のキーワード: fragment, complex, bromodomain, structural genomics, structural genomics consortium, sgc, transcription
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: O60885
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15478.83

構造登録者

Filippakopoulos, P.,Picaud, S.,Knapp, S.,von Delft, F.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,Structural Genomics Consortium (SGC) (登録日: 2016-09-11, 公開日: 2016-10-12, 最終更新日: 2024-05-08)

主引用文献

Navratilova, I.,Aristotelous, T.,Picaud, S.,Chaikuad, A.,Knapp, S.,Filappakopoulos, P.,Hopkins, A.L.
Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening.
ACS Med Chem Lett, 7:1213-1218, 2016

PubMed Abstract: The discovery of novel bromodomain inhibitors by fragment screening is complicated by the presence of dimethyl sulfoxide (DMSO), an acetyl-lysine mimetic, that can compromise the detection of low affinity fragments. We demonstrate surface plasmon resonance as a primary fragment screening approach for the discovery of novel bromodomain scaffolds, by describing a protocol to overcome the DMSO interference issue. We describe the discovery of several novel small molecules scaffolds that inhibit the bromodomains PCAF, BRD4, and CREBBP, representing canonical members of three out of the seven subfamilies of bromodomains. High-resolution crystal structures of the complexes of key fragments binding to BRD4(1), CREBBP, and PCAF were determined to provide binding mode data to aid the development of potent and selective inhibitors of PCAF, CREBBP, and BRD4.

PubMed: 27994766
DOI: 10.1021/acsmedchemlett.6b00154

実験手法

X-RAY DIFFRACTION (1.61 Å)