8OJH

Crystal structure of human CRBN-DDB1 in complex with compound 4

8OJH の概要

• エントリーDOI: 10.2210/pdb8ojh/pdb
• 分子名称: DNA damage-binding protein 1, Protein cereblon, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: e3-ligase, degradation, glue, protac, protein binding
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 175811.61

構造登録者

Cabry, M.P.,Le Bihan, Y.-V.,van Montfort, R.L.M. (登録日: 2023-03-24, 公開日: 2023-07-19, 最終更新日: 2023-12-13)

主引用文献

Bouguenina, H.,Scarpino, A.,O'Hanlon, J.A.,Warne, J.,Wang, H.Z.,Wah Hak, L.C.,Sadok, A.,McAndrew, P.C.,Stubbs, M.,Pierrat, O.A.,Hahner, T.,Cabry, M.P.,Le Bihan, Y.V.,Mitsopoulos, C.,Sialana, F.J.,Roumeliotis, T.I.,Burke, R.,van Montfort, R.L.M.,Choudhari, J.,Chopra, R.,Caldwell, J.J.,Collins, I.
A Degron Blocking Strategy Towards Improved CRL4 CRBN Recruiting PROTAC Selectivity.
Chembiochem, 24:e202300351-e202300351, 2023

PubMed Abstract: Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4 recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4 recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo-substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4 neo-substrates to attenuate and indeed remove this monovalent degradation function in well-known CRL4 molecular glues degraders, namely CC-885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9-A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC-induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.

PubMed: 37418539
DOI: 10.1002/cbic.202300351

実験手法

X-RAY DIFFRACTION (2.72 Å)