9B9W

Crystal structure of the ternary complex of DCAF1 and WDR5 with PROTAC, OICR-40792

This is a non-PDB format compatible entry.

Summary for 9B9W

• Entry DOI: 10.2210/pdb9b9w/pdb
• Descriptor: WD repeat-containing protein 5, DDB1- and CUL4-associated factor 1, (4P)-N-[(1R)-3-amino-1-(3-chloro-4-fluorophenyl)-3-oxopropyl]-4-(4-chloro-2-fluorophenyl)-5-[(25E)-1-{(1P)-6-fluoro-3'-[4-fluoro-2-(trifluoromethyl)benzamido]-4'-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl][1,1'-biphenyl]-3-yl}-1,24-dioxo-5,8,11,14,17,20-hexaoxa-2,23-diazahexacos-25-en-26-yl]-1H-pyrrole-3-carboxamide, ... (4 entities in total)
• Functional Keywords: e3 ligase, adaptor, protac, wdr, ternary complex, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 76076.23

Authors

Mabanglo, M.F.,Wilson, B.J.,Mamai, A.,Hoffer, L.,Al-awar, R.,Vedadi, M. (deposition date: 2024-04-03, release date: 2024-11-06, Last modification date: 2024-12-04)

Primary citation

Mabanglo, M.F.,Wilson, B.,Noureldin, M.,Kimani, S.W.,Mamai, A.,Krausser, C.,Gonzalez-Alvarez, H.,Srivastava, S.,Mohammed, M.,Hoffer, L.,Chan, M.,Avrumutsoae, J.,Li, A.S.M.,Hajian, T.,Tucker, S.,Green, S.,Szewczyk, M.,Barsyte-Lovejoy, D.,Santhakumar, V.,Ackloo, S.,Loppnau, P.,Li, Y.,Seitova, A.,Kiyota, T.,Wang, J.G.,Prive, G.G.,Kuntz, D.A.,Patel, B.,Rathod, V.,Vala, A.,Rout, B.,Aman, A.,Poda, G.,Uehling, D.,Ramnauth, J.,Halabelian, L.,Marcellus, R.,Al-Awar, R.,Vedadi, M.
Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity.
Nat Commun, 15:10165-10165, 2024

PubMed Abstract: Proteolysis-targeting chimeras (PROTACs) have been explored for the degradation of drug targets for more than two decades. However, only a handful of E3 ligase substrate receptors have been efficiently used. Downregulation and mutation of these receptors would reduce the effectiveness of such PROTACs. We recently developed potent ligands for DCAF1, a substrate receptor of EDVP and CUL4 E3 ligases. Here, we focus on DCAF1 toward the development of PROTACs for WDR5, a drug target in various cancers. We report four DCAF1-based PROTACs with endogenous and exogenous WDR5 degradation effects and high-resolution crystal structures of the ternary complexes of DCAF1-PROTAC-WDR5. The structures reveal detailed insights into the interaction of DCAF1 with various WDR5-PROTACs, indicating a significant role of DCAF1 loops in providing needed surface plasticity, and reflecting the mechanism by which DCAF1 functions as a substrate receptor for E3 ligases with diverse sets of substrates.

PubMed: 39580491
DOI: 10.1038/s41467-024-54500-x

Experimental method

X-RAY DIFFRACTION (1.92 Å)