6ZHC

PROTAC6 mediated complex of VHL:EloB:EloC and Bcl-xL

これはPDB形式変換不可エントリーです。

6ZHC の概要

• エントリーDOI: 10.2210/pdb6zhc/pdb
• 分子名称: von Hippel-Lindau disease tumor suppressor, Elongin-B, Elongin-C, ... (9 entities in total)
• 機能のキーワード: protac complex, targeted degradation, ubiquitin ligase, bifunctional ligand, e3 ligase, bcl-xl, 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: 70560.51

構造登録者

Chung, C. (登録日: 2020-06-22, 公開日: 2020-08-05, 最終更新日: 2024-01-24)

主引用文献

Chung, C.W.,Dai, H.,Fernandez, E.,Tinworth, C.P.,Churcher, I.,Cryan, J.,Denyer, J.,Harling, J.D.,Konopacka, A.,Queisser, M.A.,Tame, C.J.,Watt, G.,Jiang, F.,Qian, D.,Benowitz, A.B.
Structural Insights into PROTAC-Mediated Degradation of Bcl-xL.
Acs Chem.Biol., 15:2316-2323, 2020

PubMed Abstract: The Bcl-2 family of proteins, such as Bcl-xL and Bcl-2, play key roles in cancer cell survival. Structural studies of Bcl-xL formed the foundation for the development of the first Bcl-2 family inhibitors and FDA approved drugs. Recently, teolysis rgeting himeras (PROTACs) that degrade Bcl-xL have been proposed as a therapeutic modality with the potential to enhance potency and reduce toxicity versus antagonists. However, no ternary complex structures of Bcl-xL with a PROTAC and an E3 ligase have been successfully determined to guide this approach. Herein, we report the design, characterization, and X-ray structure of a VHL E3 ligase-recruiting Bcl-xL PROTAC degrader. The 1.9 Å heterotetrameric structure, composed of (ElonginB:ElonginC:VHL):PROTAC:Bcl-xL, reveals an extensive network of neo-interactions, between the E3 ligase and the target protein, and between noncognate parts of the PROTAC and partner proteins. This work illustrates the challenges associated with the rational design of bifunctional molecules where interactions involve composite interfaces.

PubMed: 32697072
DOI: 10.1021/acschembio.0c00266

実験手法

X-RAY DIFFRACTION (1.92 Å)