8EI9

Crystal structure of beta-catenin and the MDM2 p53-binding domain in complex with H332, a Helicon Polypeptide

8EI9 の概要

• エントリーDOI: 10.2210/pdb8ei9/pdb
• 分子名称: H332, Catenin beta-1, E3 ubiquitin-protein ligase Mdm2, ... (4 entities in total)
• 機能のキーワード: e3 ligase, complex, stapled peptide, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 71872.38

構造登録者

Li, K.,Travaline, T.L.,Swiecicki, J.-M.,Tokareva, O.S.,Thomson, T.M.,Verdine, G.L.,McGee, J.H. (登録日: 2022-09-14, 公開日: 2023-10-25, 最終更新日: 2023-11-15)

主引用文献

Tokareva, O.S.,Li, K.,Travaline, T.L.,Thomson, T.M.,Swiecicki, J.M.,Moussa, M.,Ramirez, J.D.,Litchman, S.,Verdine, G.L.,McGee, J.H.
Recognition and reprogramming of E3 ubiquitin ligase surfaces by alpha-helical peptides.
Nat Commun, 14:6992-6992, 2023

PubMed Abstract: Molecules that induce novel interactions between proteins hold great promise for the study of biological systems and the development of therapeutics, but their discovery has been limited by the complexities of rationally designing interactions between three components, and because known binders to each protein are typically required to inform initial designs. Here, we report a general and rapid method for discovering α-helically constrained (Helicon) polypeptides that cooperatively induce the interaction between two target proteins without relying on previously known binders or an intrinsic affinity between the proteins. We show that Helicons are capable of binding every major class of E3 ubiquitin ligases, which are of great biological and therapeutic interest but remain largely intractable to targeting by small molecules. We then describe a phage-based screening method for discovering "trimerizer" Helicons, and apply it to reprogram E3s to cooperatively bind an enzyme (PPIA), a transcription factor (TEAD4), and a transcriptional coactivator (β-catenin).

PubMed: 37914719
DOI: 10.1038/s41467-023-42395-z

実験手法

X-RAY DIFFRACTION (3.9 Å)