4MEP

Crystal Structure of the first bromodomain of human BRD4 in complex with a 3-chloro-pyridone ligand

4MEP の概要

• エントリーDOI: 10.2210/pdb4mep/pdb
• 関連するPDBエントリー: 4MEN 4MEO 4MEQ
• 分子名称: Bromodomain-containing protein 4, 3-chloro-5-[1-(3-methylpyridin-2-yl)-3-phenyl-1H-1,2,4-triazol-5-yl]pyridin-2(1H)-one (3 entities in total)
• 機能のキーワード: brd4, cap, hunk1, mcap, mitotic chromosome associated protein, brd, small molecule inhibitor, structural genomics consortium, sgc, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 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: 15463.18

構造登録者

Filippakopoulos, P.,Picaud, S.,Felletar, I.,Martin, S.,Fedorov, O.,Vidler, L.R.,Brown, N.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Bountra, C.,Hoelder, S.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2013-08-27, 公開日: 2013-09-25, 最終更新日: 2023-09-20)

主引用文献

Vidler, L.R.,Filippakopoulos, P.,Fedorov, O.,Picaud, S.,Martin, S.,Tomsett, M.,Woodward, H.,Brown, N.,Knapp, S.,Hoelder, S.
Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening.
J.Med.Chem., 56:8073-8088, 2013

PubMed Abstract: Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.

PubMed: 24090311
DOI: 10.1021/jm4011302

実験手法

X-RAY DIFFRACTION (1.85 Å)