8Z6C

Crystal structure of HDGFRP2 PWWP domain in complex with 4-(4-bromo-1H-pyrazol-3-yl) pyridine

これはPDB形式変換不可エントリーです。

8Z6C の概要

• エントリーDOI: 10.2210/pdb8z6c/pdb
• 分子名称: Hepatoma-derived growth factor-related protein 2, 4-(4-bromanyl-1~{H}-pyrazol-3-yl)pyridine, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: hepatoma-derived growth factor-related protein 2, pwwp domain, hit, 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: 33124.04

構造登録者

Wei, X.,Ruan, K. (登録日: 2024-04-19, 公開日: 2025-04-23, 最終更新日: 2025-12-24)

主引用文献

Wei, X.,Li, S.,Li, Z.,Wang, L.,Fan, W.,Ruan, K.,Gao, J.
Fragment-based discovery of small molecule inhibitors of the HDGFRP2 PWWP domain.
Febs Lett., 598:2533-2543, 2024

PubMed Abstract: The PWWP domain of hepatoma-derived growth factor-related protein 2 (HDGFRP2) recognizes methylated histones to initiate the recruitment of homologous recombination repair proteins to damaged silent genes. The combined depletion of HDGFRP2 and its paralog PSIP1 effectively impedes the onset and progression of diffuse intrinsic pontine glioma (DIPG). Here, we discovered varenicline and 4-(4-bromo-1H-pyrazol-3-yl) pyridine (BPP) as inhibitors of the HDGFRP2 PWWP domain through a fragment-based screening method. The complex crystal structures reveal that both Varenicline and BPP engage with the aromatic cage of the HDGFRP2 PWWP domain, albeit via unique binding mechanisms. Notably, BPP represents the first single-digit micromolar inhibitor of the HDGFRP2 PWWP domain with a high ligand efficiency. As a dual inhibitor targeting both HDGFRP2 and PSIP1 PWWP domains, BPP offers an exceptional foundation for further optimization into a chemical tool to dissect the synergetic function of HDGFRP2 and PSIP1 in DIPG pathogenesis.

PubMed: 39031937
DOI: 10.1002/1873-3468.14981

実験手法

X-RAY DIFFRACTION (1.93 Å)