8OIZ

Crystal structure of human CRBN-DDB1 in complex with Pomalidomide

Summary for 8OIZ

• Entry DOI: 10.2210/pdb8oiz/pdb
• Descriptor: DNA damage-binding protein 1, Protein cereblon, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: e3-ligase, degradation, glue, protac, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 175595.39

Authors

Le Bihan, Y.-V.,Cabry, M.P.,van Montfort, R.L.M. (deposition date: 2023-03-23, release date: 2023-07-19, Last modification date: 2023-12-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)