8FY2

E3:PROTAC:target ternary complex structure (VCB/WH244/BCL-2)

8FY2 の概要

• エントリーDOI: 10.2210/pdb8fy2/pdb
• 分子名称: von Hippel-Lindau disease tumor suppressor, Elongin-B, Elongin-C, ... (5 entities in total)
• 機能のキーワード: ternary complex, degrader, 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: 69420.14

構造登録者

Nayak, D.,Lv, D.,Yuan, Y.,Zhang, P.,Hu, W.,Ruben, E.,Lv, Z.,Sung, P.,Hromas, R.,Zheng, G.,Zhou, D.,Olsen, S.K. (登録日: 2023-01-25, 公開日: 2024-04-10)

主引用文献

Nayak, D.,Lv, D.,Yuan, Y.,Zhang, P.,Hu, W.,Nayak, A.,Ruben, E.A.,Lv, Z.,Sung, P.,Hromas, R.,Zheng, G.,Zhou, D.,Olsen, S.K.
Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL.
Nat Commun, 15:2743-2743, 2024

PubMed Abstract: Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determine crystal structures of VHL/753b/BCL-xL and VHL/753b/BCL-2 ternary complexes. The two ternary complexes exhibit markedly different architectures that are accompanied by distinct networks of interactions at the VHL/753b-linker/target interfaces. The importance of these interfacial contacts is validated via functional analysis and informed subsequent rational and structure-guided design focused on the 753b linker and BCL-2/BCL-xL warhead. This results in the design of a degrader, WH244, with enhanced potency to degrade BCL-xL/BCL-2 in cells. Using biophysical assays followed by in cell activities, we are able to explain the enhanced target degradation of BCL-xL/BCL-2 in cells. Most PROTACs are empirically designed and lack structural studies, making it challenging to understand their modes of action and specificity. Our work presents a streamlined approach that combines rational design and structure-based insights backed with cell-based studies to develop effective PROTAC-based cancer therapeutics.

PubMed: 38548768
DOI: 10.1038/s41467-024-46922-4

実験手法

X-RAY DIFFRACTION (2.98 Å)