Nature Communications (Nov 2024)
Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity
- Mark F. Mabanglo,
- Brian Wilson,
- Mahmoud Noureldin,
- Serah W. Kimani,
- Ahmed Mamai,
- Chiara Krausser,
- Héctor González-Álvarez,
- Smriti Srivastava,
- Mohammed Mohammed,
- Laurent Hoffer,
- Manuel Chan,
- Jamie Avrumutsoae,
- Alice Shi Ming Li,
- Taraneh Hajian,
- Sarah Tucker,
- Stuart Green,
- Magdalena Szewczyk,
- Dalia Barsyte-Lovejoy,
- Vijayaratnam Santhakumar,
- Suzanne Ackloo,
- Peter Loppnau,
- Yanjun Li,
- Almagul Seitova,
- Taira Kiyota,
- Jue George Wang,
- Gilbert G. Privé,
- Douglas A. Kuntz,
- Bhashant Patel,
- Vaibhavi Rathod,
- Anand Vala,
- Bhimsen Rout,
- Ahmed Aman,
- Gennady Poda,
- David Uehling,
- Jailall Ramnauth,
- Levon Halabelian,
- Richard Marcellus,
- Rima Al-awar,
- Masoud Vedadi
Affiliations
- Mark F. Mabanglo
- Drug Discovery Program, Ontario Institute for Cancer Research
- Brian Wilson
- Drug Discovery Program, Ontario Institute for Cancer Research
- Mahmoud Noureldin
- Drug Discovery Program, Ontario Institute for Cancer Research
- Serah W. Kimani
- Structural Genomics Consortium, University of Toronto
- Ahmed Mamai
- Drug Discovery Program, Ontario Institute for Cancer Research
- Chiara Krausser
- Drug Discovery Program, Ontario Institute for Cancer Research
- Héctor González-Álvarez
- Drug Discovery Program, Ontario Institute for Cancer Research
- Smriti Srivastava
- Drug Discovery Program, Ontario Institute for Cancer Research
- Mohammed Mohammed
- Drug Discovery Program, Ontario Institute for Cancer Research
- Laurent Hoffer
- Drug Discovery Program, Ontario Institute for Cancer Research
- Manuel Chan
- Drug Discovery Program, Ontario Institute for Cancer Research
- Jamie Avrumutsoae
- Drug Discovery Program, Ontario Institute for Cancer Research
- Alice Shi Ming Li
- Drug Discovery Program, Ontario Institute for Cancer Research
- Taraneh Hajian
- Drug Discovery Program, Ontario Institute for Cancer Research
- Sarah Tucker
- Drug Discovery Program, Ontario Institute for Cancer Research
- Stuart Green
- Structural Genomics Consortium, University of Toronto
- Magdalena Szewczyk
- Structural Genomics Consortium, University of Toronto
- Dalia Barsyte-Lovejoy
- Structural Genomics Consortium, University of Toronto
- Vijayaratnam Santhakumar
- Structural Genomics Consortium, University of Toronto
- Suzanne Ackloo
- Structural Genomics Consortium, University of Toronto
- Peter Loppnau
- Structural Genomics Consortium, University of Toronto
- Yanjun Li
- Structural Genomics Consortium, University of Toronto
- Almagul Seitova
- Structural Genomics Consortium, University of Toronto
- Taira Kiyota
- Drug Discovery Program, Ontario Institute for Cancer Research
- Jue George Wang
- Drug Discovery Program, Ontario Institute for Cancer Research
- Gilbert G. Privé
- Princess Margaret Cancer Centre, University Health Network
- Douglas A. Kuntz
- Princess Margaret Cancer Centre, University Health Network
- Bhashant Patel
- Piramal Discovery Solutions, Pharmaceutical Special Economic Zone
- Vaibhavi Rathod
- Piramal Discovery Solutions, Pharmaceutical Special Economic Zone
- Anand Vala
- Piramal Discovery Solutions, Pharmaceutical Special Economic Zone
- Bhimsen Rout
- Piramal Discovery Solutions, Pharmaceutical Special Economic Zone
- Ahmed Aman
- Drug Discovery Program, Ontario Institute for Cancer Research
- Gennady Poda
- Drug Discovery Program, Ontario Institute for Cancer Research
- David Uehling
- Drug Discovery Program, Ontario Institute for Cancer Research
- Jailall Ramnauth
- Drug Discovery Program, Ontario Institute for Cancer Research
- Levon Halabelian
- Structural Genomics Consortium, University of Toronto
- Richard Marcellus
- Drug Discovery Program, Ontario Institute for Cancer Research
- Rima Al-awar
- Drug Discovery Program, Ontario Institute for Cancer Research
- Masoud Vedadi
- Drug Discovery Program, Ontario Institute for Cancer Research
- DOI
- https://doi.org/10.1038/s41467-024-54500-x
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 17
Abstract
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.
