8G46

Cryo-EM structure of DDB1deltaB-DDA1-DCAF16-BRD4(BD2)-MMH2

8G46 の概要

• エントリーDOI: 10.2210/pdb8g46/pdb
• EMDBエントリー: 29714
• 分子名称: DNA damage-binding protein 1, DDB1- and CUL4-associated factor 16, Bromodomain-containing protein 4, ... (7 entities in total)
• 機能のキーワード: e3 ligase, ubiquitin, degrader, targeted protein degradation, ligase
• 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: 148651.12

構造登録者

Ma, M.W.,Hunkeler, M.,Jin, C.Y.,Fischer, E.S. (登録日: 2023-02-08, 公開日: 2023-03-08, 最終更新日: 2024-10-23)

主引用文献

Li, Y.D.,Ma, M.W.,Hassan, M.M.,Hunkeler, M.,Teng, M.,Puvar, K.,Lumpkin, R.,Sandoval, B.,Jin, C.Y.,Ficarro, S.B.,Wang, M.Y.,Xu, S.,Groendyke, B.J.,Sigua, L.H.,Tavares, I.,Zou, C.,Tsai, J.M.,Park, P.M.C.,Yoon, H.,Majewski, F.C.,Marto, J.A.,Qi, J.,Nowak, R.P.,Donovan, K.A.,Slabicki, M.,Gray, N.S.,Fischer, E.S.,Ebert, B.L.
Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders.
Biorxiv, 2023

PubMed Abstract: Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a -labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4 ligase to the second bromodomain of BRD4 (BRD4). BRD4, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4 revealed that the loop conformation around BRD4, rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes "template-assisted covalent modification" as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.

PubMed: 36824856
DOI: 10.1101/2023.02.14.528208

実験手法

ELECTRON MICROSCOPY (2.2 Å)