7AQT

NMR2 structure of BRD4-BD2 in complex with iBET-762

7AQT の概要

• エントリーDOI: 10.2210/pdb7aqt/pdb
• NMR情報: BMRB: 34566
• 分子名称: Bromodomain-containing protein 4, 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide (2 entities in total)
• 機能のキーワード: brd4, bd2, bromodomain, ibet-762, nmr2, oncoprotein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13173.69

構造登録者

Orts, J.,Torres, F.,Milbradt, A.G.,Walser, R. (登録日: 2020-10-23, 公開日: 2022-03-02, 最終更新日: 2024-06-19)

主引用文献

Torres, F.,Walser, R.,Kaderli, J.,Rossi, E.,Bobby, R.,Packer, M.J.,Sarda, S.,Walker, G.,Hitchin, J.R.,Milbradt, A.G.,Orts, J.
NMR Molecular Replacement Provides New Insights into Binding Modes to Bromodomains of BRD4 and TRIM24.
J.Med.Chem., 65:5565-5574, 2022

PubMed Abstract: Structure-based drug discovery (SBDD) largely relies on structural information from X-ray crystallography because traditional NMR structure calculation methods are too time consuming to be aligned with typical drug discovery timelines. The recently developed NMR molecular replacement (MR) method dramatically reduces the time needed to generate ligand-protein complex structures using published structures (apo or holo) of the target protein and treating all observed NOEs as ambiguous restraints, bypassing the laborious process of obtaining sequence-specific resonance assignments for the protein target. We apply this method to two therapeutic targets, the bromodomain of TRIM24 and the second bromodomain of BRD4. We show that the MR methodology can guide SBDD by rationalizing the observed SAR. We also demonstrate that new types of restraints and selective methyl labeling have the potential to dramatically reduce "time to structure" and extend the method to targets beyond the reach of traditional NMR structure elucidation.

PubMed: 35357834
DOI: 10.1021/acs.jmedchem.1c01703

実験手法

SOLUTION NMR