6SIS

Crystal structure of macrocyclic PROTAC 1 in complex with the second bromodomain of human Brd4 and pVHL:ElonginC:ElonginB

6SIS の概要

• エントリーDOI: 10.2210/pdb6sis/pdb
• 分子名称: Bromodomain-containing protein 4, Elongin-B, Elongin-C, ... (6 entities in total)
• 機能のキーワード: protac complex, macrocycle, targeted degradation, ligase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 115212.83

構造登録者

Hughes, S.J.,Testa, A.,Ciulli, A. (登録日: 2019-08-10, 公開日: 2019-12-04, 最終更新日: 2024-01-24)

主引用文献

Testa, A.,Hughes, S.J.,Lucas, X.,Wright, J.E.,Ciulli, A.
Structure-Based Design of a Macrocyclic PROTAC.
Angew.Chem.Int.Ed.Engl., 59:1727-1734, 2020

PubMed Abstract: Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Herein, we report the design and synthesis of a macrocyclic PROTAC by adding a cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second bromodomain of Brd4 validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets.

PubMed: 31746102
DOI: 10.1002/anie.201914396

実験手法

X-RAY DIFFRACTION (3.5 Å)