8XV7

Crystal structure of TTD-PHD domain of UHRF1 in complex with hStella peptide (residues 75-121)

8XV7 の概要

• エントリーDOI: 10.2210/pdb8xv7/pdb
• 分子名称: E3 ubiquitin-protein ligase UHRF1, Developmental pluripotency-associated protein 3, ZINC ION, ... (6 entities in total)
• 機能のキーワード: inhibitor, complex, gene regulation
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 129721.93

構造登録者

Du, X.,Gan, Q.,Xu, J.,Liu, J. (登録日: 2024-01-14, 公開日: 2024-11-06, 最終更新日: 2025-02-19)

主引用文献

Bai, W.,Xu, J.,Gu, W.,Wang, D.,Cui, Y.,Rong, W.,Du, X.,Li, X.,Xia, C.,Gan, Q.,He, G.,Guo, H.,Deng, J.,Wu, Y.,Yen, R.C.,Yegnasubramanian, S.,Rothbart, S.B.,Luo, C.,Wu, L.,Liu, J.,Baylin, S.B.,Kong, X.
Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy.
Nat Commun, 16:474-474, 2025

PubMed Abstract: UHRF1 maintains DNA methylation by recruiting DNA methyltransferases to chromatin. In mouse, these dynamics are potently antagonized by a natural UHRF1 inhibitory protein STELLA, while the comparable effects of its human ortholog are insufficiently characterized, especially in cancer cells. Herein, we demonstrate that human STELLA (hSTELLA) is inadequate, while mouse STELLA (mSTELLA) is fully proficient in inhibiting the abnormal DNA methylation and oncogenic functions of UHRF1 in human cancer cells. Structural studies reveal a region of low sequence homology between these STELLA orthologs that allows mSTELLA but not hSTELLA to bind tightly and cooperatively to the essential histone-binding, linked tandem Tudor domain and plant homeodomain (TTD-PHD) of UHRF1, thus mediating ortholog-specific UHRF1 inhibition. For translating these findings to cancer therapy, we use a lipid nanoparticle (LNP)-mediated mRNA delivery approach in which the short mSTELLA, but not hSTELLA regions are required to reverse cancer-specific DNA hypermethylation and impair colorectal cancer tumorigenicity.

PubMed: 39774694
DOI: 10.1038/s41467-024-55481-7

実験手法

X-RAY DIFFRACTION (2.25 Å)