4A9I

N-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 3-methyl-1,2,3,4- tetrahydroquinazolin-2-one

4A9I の概要

• エントリーDOI: 10.2210/pdb4a9i/pdb
• 関連するPDBエントリー: 4A9E 4A9F 4A9H 4A9J 4A9K 4A9L 4A9M
• 分子名称: BROMODOMAIN CONTAINING 2, 1-[1-(PYRIDIN-2-YL)INDOLIZIN-3-YL]ETHAN-1-ONE, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, histone, epigenetic reader, signaling protein
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 54788.27

構造登録者

Chung, C.W.,Bamborough, P. (登録日: 2011-11-26, 公開日: 2012-01-11, 最終更新日: 2024-05-08)

主引用文献

Chung, C.W.,Dean, A.W.,Woolven, J.M.,Bamborough, P.
Fragment-Based Discovery of Bromodomain Inhibitors Part 1: Inhibitor Binding Modes and Implications for Lead Discovery.
J.Med.Chem., 55:576-, 2012

PubMed Abstract: Bromodomain-containing proteins are key epigenetic regulators of gene transcription and readers of the histone code. However, the therapeutic benefits of modulating this target class are largely unexplored due to the lack of suitable chemical probes. This article describes the generation of lead molecules for the BET bromodomains through screening a fragment set chosen using structural insights and computational approaches. Analysis of 40 BRD2/fragment X-ray complexes highlights both shared and disparate interaction features that may be exploited for affinity and selectivity. Six representative crystal structures are then exemplified in detail. Two of the fragments are completely new bromodomain chemotypes, and three have never before been crystallized in a bromodomain, so our results significantly extend the limited public knowledge-base of crystallographic small molecule/bromodomain interactions. Certain fragments (including paracetamol) bind in a consistent mode to different bromodomains such as CREBBP, suggesting their potential to act as generic bromodomain templates. An important implication is that the bromodomains are not only a phylogenetic family but also a system in which chemical and structural knowledge of one bromodomain gives insights transferrable to others.

PubMed: 22136404
DOI: 10.1021/JM201320W

実験手法

X-RAY DIFFRACTION (2.25 Å)