8G1Q

Co-crystal structure of Compound 1 in complex with the bromodomain of human SMARCA4 and pVHL:ElonginC:ElonginB

8G1Q の概要

• エントリーDOI: 10.2210/pdb8g1q/pdb
• 関連するPDBエントリー: 8G1P
• 分子名称: Transcription activator BRG1, Elongin-B, Elongin-C, ... (8 entities in total)
• 機能のキーワード: ternary complex, protacs, transcription, gene regulation
• 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: 56767.95

構造登録者

Ghimire Rijal, S.,Wurz, R.P.,Vaish, A. (登録日: 2023-02-02, 公開日: 2023-07-26, 最終更新日: 2023-08-30)

主引用文献

Wurz, R.P.,Rui, H.,Dellamaggiore, K.,Ghimire-Rijal, S.,Choi, K.,Smither, K.,Amegadzie, A.,Chen, N.,Li, X.,Banerjee, A.,Chen, Q.,Mohl, D.,Vaish, A.
Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation.
Nat Commun, 14:4177-4177, 2023

PubMed Abstract: Targeted protein degradation via "hijacking" of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design of PROTACs is challenging; multiple steps involved in PROTAC-induced degradation make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and degradation by employing von Hippel-Lindau protein (VHL) recruiting PROTACs for two different target proteins, SMARCA2 and BRD4. Ternary-complex attributes and degradation activity parameters are evaluated by varying components of the PROTAC's architecture. Ternary complex binding affinity and cooperativity correlates well with degradation potency and initial rates of degradation. Additionally, we develop a ternary-complex structure modeling workflow to calculate the total buried surface area at the interface, which is in agreement with the measured ternary complex binding affinity. Our findings establish a predictive framework to guide the design of potent degraders.

PubMed: 37443112
DOI: 10.1038/s41467-023-39904-5

実験手法

X-RAY DIFFRACTION (3.73 Å)