9PG9

Structure of UBR2-AF27 complex

これはPDB形式変換不可エントリーです。

9PG9 の概要

• エントリーDOI: 10.2210/pdb9pg9/pdb
• 関連するPDBエントリー: 9PG4
• 関連するBIRD辞書のPRD_ID: PRD_002579
• 分子名称: E3 ubiquitin-protein ligase UBR2, AF27 peptide, ZINC ION, ... (4 entities in total)
• 機能のキーワード: ubr, e3 ligase, peptidomimetics ligands, protein binding
• 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: 17910.28

構造登録者

Huang, S.,Wu, J.,Taylor, S.,Chen, Y. (登録日: 2025-07-07, 公開日: 2026-05-20, 最終更新日: 2026-06-10)

主引用文献

Huang, S.T.,Faouzi, A.,Thomas, N.,Wu, J.,Pestonjamasp, K.,Chen, D.H.,Ren, T.,Kuang, Y.,Taylor, S.,Chen, Y.
Development of High-Affinity Ligands for Human UBR2.
J.Med.Chem., 69:11738-11751, 2026

PubMed Abstract: UBR box-containing ubiquitin E3 ligases recognize the N-termini of their target proteins through the UBR box, and a member of the family, UBR2, has been established as a target to treat cancer- and diabetes-associated cachexia. However, the development of high-affinity small-molecule ligands for UBR2 has not been reported. We developed high-affinity UBR2 ligands through a peptidomimetic approach by incorporating unnatural amino acids to obtain ligands that bind to UBR2 with ∼ 20-40 nM and with 10-fold selectivity over UBR2's closest homologue, UBR1. High-resolution cocrystal structures (∼1.2 Å) of UBR2 in complexes with two high-affinity tripeptides revealed molecular mechanisms for their high-affinity binding. Importantly, a high-affinity UBR2 ligand effectively attenuated cancer-induced cachexia in a cellular model. Our findings demonstrate that the UBR boxes are ligandable and thus could spur interest in targeting this class of E3 ligases for developing novel therapeutic approaches for the treatment of cachexia and other illnesses.

PubMed: 42102356
DOI: 10.1021/acs.jmedchem.5c02881

実験手法

X-RAY DIFFRACTION (1.22 Å)