5YYF

Crystal structure of AF9 YEATS domain in complex with a peptide inhibitor "PHQ-H3(Q5-K9)" modified at K9 with 2-furancarboyl group

5YYF の概要

• エントリーDOI: 10.2210/pdb5yyf/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002284
• 分子名称: Protein AF-9, Peptide inhibitor PHQ-H3(Q5-K9), SULFATE ION, ... (5 entities in total)
• 機能のキーワード: yeats domain, complex, inhibitor, 2-furancarboyl group, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 35245.24

構造登録者

Li, Y.,Li, H. (登録日: 2017-12-09, 公開日: 2018-11-07, 最終更新日: 2024-10-16)

主引用文献

Li, X.,Li, X.M.,Jiang, Y.,Liu, Z.,Cui, Y.,Fung, K.Y.,van der Beelen, S.H.E.,Tian, G.,Wan, L.,Shi, X.,Allis, C.D.,Li, H.,Li, Y.,Li, X.D.
Structure-guided development of YEATS domain inhibitors by targeting pi-pi-pi stacking.
Nat. Chem. Biol., 14:1140-1149, 2018

PubMed Abstract: Chemical probes of epigenetic 'readers' of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in normal physiology and disease pathogenesis. Here we report the development of the first class of chemical probes of YEATS domains, newly identified 'readers' of histone lysine acetylation (Kac) and crotonylation (Kcr). Guided by the structural analysis of a YEATS-Kcr complex, we developed a series of peptide-based inhibitors of YEATS domains by targeting a unique π-π-π stacking interaction at the proteins' Kcr recognition site. Further structure optimization resulted in the selective inhibitors preferentially binding to individual YEATS-containing proteins including AF9 and ENL with submicromolar affinities. We demonstrate that one of the ENL YEATS-selective inhibitors, XL-13m, engages with endogenous ENL, perturbs the recruitment of ENL onto chromatin, and synergizes the BET and DOT1L inhibition-induced downregulation of oncogenes in MLL-rearranged acute leukemia.

PubMed: 30374167
DOI: 10.1038/s41589-018-0144-y

実験手法

X-RAY DIFFRACTION (1.903 Å)