8ROY

Structure of the human DDB1-DDA1-DCAF15 E3 ubiquitin ligase bound to compound furan 24

This is a non-PDB format compatible entry.

Summary for 8ROY

• Entry DOI: 10.2210/pdb8roy/pdb
• EMDB information: 19407
• Descriptor: DDB1- and CUL4-associated factor 15, DNA damage-binding protein 1, DET1- and DDB1-associated protein 1, ... (4 entities in total)
• Functional Keywords: e3 ligase, complex, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 172538.38

Authors

Shilliday, F.,Lucas, S.C.C.,Richter, M.,Michaelides, I.N.,Fusani, L. (deposition date: 2024-01-12, release date: 2024-04-03, Last modification date: 2024-10-23)

Primary citation

Lucas, S.C.C.,Ahmed, A.,Ashraf, S.N.,Argyrou, A.,Bauer, M.R.,De Donatis, G.M.,Demanze, S.,Eisele, F.,Fusani, L.,Hock, A.,Kadamur, G.,Li, S.,Macmillan-Jones, A.,Michaelides, I.N.,Phillips, C.,Rehnstrom, M.,Richter, M.,Rodrigo-Brenni, M.C.,Shilliday, F.,Wang, P.,Storer, R.I.
Optimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders.
J.Med.Chem., 67:5538-5566, 2024

PubMed Abstract: Unlocking novel E3 ligases for use in heterobifunctional PROTAC degraders is of high importance to the pharmaceutical industry. Over-reliance on the current suite of ligands used to recruit E3 ligases could limit the potential of their application. To address this, potent ligands for DCAF15 were optimized using cryo-EM supported, structure-based design to improve on micromolar starting points. A potent binder, compound , was identified and subsequently conjugated into PROTACs against multiple targets. Following attempts on degrading a number of proteins using DCAF15 recruiting PROTACs, only degradation of BRD4 was observed. Deconvolution of the mechanism of action showed that this degradation was not mediated by DCAF15, thereby highlighting both the challenges faced when trying to expand the toolbox of validated E3 ligase ligands for use in PROTAC degraders and the pitfalls of using BRD4 as a model substrate.

PubMed: 38513086
DOI: 10.1021/acs.jmedchem.3c02136

Experimental method

ELECTRON MICROSCOPY (3.1 Å)