Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity
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.
Authors
- Taira Kiyota (ORCID: https://orcid.org/0000-0001-6313-3482)
- Serah Kimani (ORCID: https://orcid.org/0000-0002-6960-3833)
- P. Loppnau (ORCID: https://orcid.org/0009-0004-0002-355X)
- Levon Halabelian (ORCID: https://orcid.org/0000-0003-4361-3619)
- Sarah J. Tucker (ORCID: https://orcid.org/0000-0003-0541-0853)
- R. Al-Awar
- Dalia Baršytė-Lovejoy (ORCID: https://orcid.org/0000-0002-6560-9621)
- Mark F. Mabanglo (ORCID: https://orcid.org/0000-0003-4671-4159)
- Magdalena M. Szewczyk (ORCID: https://orcid.org/0000-0001-9243-1630)
- Masoud Vedadi (ORCID: https://orcid.org/0000-0002-0574-0169)
- David Uehling (ORCID: https://orcid.org/0000-0002-9748-0500)
- D.A. Kuntz (ORCID: https://orcid.org/0000-0003-3584-4804)
- Manuel Chan
- Ahmed Mamai
- Taraneh Hajian (ORCID: https://orcid.org/0000-0002-3248-6266)
- Jue Wang (ORCID: https://orcid.org/0000-0002-4162-8852)
- Almagul Seitova
- Vijayaratnam Santhakumar (ORCID: https://orcid.org/0000-0002-7001-557X)
- Gilbert G. Privé (ORCID: https://orcid.org/0000-0002-0712-4319)
- Ahmed M. Aman (ORCID: https://orcid.org/0000-0002-0275-205X)
- Mahmoud Noureldin
- Alice Shi Ming Li (ORCID: https://orcid.org/0000-0003-1093-9698)
- Richard Marcellus (ORCID: https://orcid.org/0009-0005-6946-6954)
- Stuart R. Green (ORCID: https://orcid.org/0000-0002-2960-9683)
- Héctor González-Álvarez (ORCID: https://orcid.org/0000-0001-6990-169X)
- Brian C. Wilson (ORCID: https://orcid.org/0000-0001-5543-666X)
- Anand Vala (ORCID: https://orcid.org/0000-0002-2186-820X)
- Suzanne Ackloo (ORCID: https://orcid.org/0000-0002-9696-1839)
- Yanjun Li (ORCID: https://orcid.org/0000-0002-9512-5265)
- Mohammed Mohammed (ORCID: https://orcid.org/0000-0003-2958-2019)
- Laurent Hoffer (ORCID: https://orcid.org/0000-0003-1906-7128)
- Jamie Avrumutsoae
- Chiara Krausser
- Jailall Ramnauth
- Bhimsen Rout
- Gennady Poda
- Bhashant Patel
- Vaibhavi Rathod
- Smriti Srivastava
Institutions
- Ontario Institute for Cancer Research (CA)
- University Health Network (CA)
- University of Toronto (CA)
- Princess Margaret Cancer Centre (CA)
- Structural Genomics Consortium (CA)
- Piramal (India) (IN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-23
- DOI
- https://doi.org/10.1038/s41467-024-54500-x
- Citations
- 28
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 6.55
Funders
- Bristol-Myers Squibb
- Pfizer
- Bayer
- Canadian Light Source
- McGill University
- Genome Canada
- Merck KGaA
- Ontario Genomics
- European Federation of Pharmaceutical Industries and Associations
- Government of Ontario
- Ontario Genomics Institute
- Genentech
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada