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 () and Masoud Vedadi ()
Additional contact information
Mark F. Mabanglo: Ontario Institute for Cancer Research
Brian Wilson: Ontario Institute for Cancer Research
Mahmoud Noureldin: Ontario Institute for Cancer Research
Serah W. Kimani: University of Toronto
Ahmed Mamai: Ontario Institute for Cancer Research
Chiara Krausser: Ontario Institute for Cancer Research
Héctor González-Álvarez: Ontario Institute for Cancer Research
Smriti Srivastava: Ontario Institute for Cancer Research
Mohammed Mohammed: Ontario Institute for Cancer Research
Laurent Hoffer: Ontario Institute for Cancer Research
Manuel Chan: Ontario Institute for Cancer Research
Jamie Avrumutsoae: Ontario Institute for Cancer Research
Alice Shi Ming Li: Ontario Institute for Cancer Research
Taraneh Hajian: Ontario Institute for Cancer Research
Sarah Tucker: Ontario Institute for Cancer Research
Stuart Green: University of Toronto
Magdalena Szewczyk: University of Toronto
Dalia Barsyte-Lovejoy: University of Toronto
Vijayaratnam Santhakumar: University of Toronto
Suzanne Ackloo: University of Toronto
Peter Loppnau: University of Toronto
Yanjun Li: University of Toronto
Almagul Seitova: University of Toronto
Taira Kiyota: Ontario Institute for Cancer Research
Jue George Wang: Ontario Institute for Cancer Research
Gilbert G. Privé: University Health Network
Douglas A. Kuntz: University Health Network
Bhashant Patel: Pharmaceutical Special Economic Zone
Vaibhavi Rathod: Pharmaceutical Special Economic Zone
Anand Vala: Pharmaceutical Special Economic Zone
Bhimsen Rout: Pharmaceutical Special Economic Zone
Ahmed Aman: Ontario Institute for Cancer Research
Gennady Poda: Ontario Institute for Cancer Research
David Uehling: Ontario Institute for Cancer Research
Jailall Ramnauth: Ontario Institute for Cancer Research
Levon Halabelian: University of Toronto
Richard Marcellus: Ontario Institute for Cancer Research
Rima Al-awar: Ontario Institute for Cancer Research
Masoud Vedadi: Ontario Institute for Cancer Research

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-54500-x

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