2. Academic Validation
  3. Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity

Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity

  • Nat Commun. 2024 Nov 23;15(1):10165. doi: 10.1038/s41467-024-54500-x.
Mark F Mabanglo # 1,  Brian Wilson # 1,  Mahmoud Noureldin # 1,  Serah W Kimani 2,  Ahmed Mamai 1,  Chiara Krausser 1,  Héctor González-Álvarez 1 3,  Smriti Srivastava 1,  Mohammed Mohammed 1,  Laurent Hoffer 1,  Manuel Chan 1,  Jamie Avrumutsoae 1,  Alice Shi Ming Li 1 3,  Taraneh Hajian 1,  Sarah Tucker 1,  Stuart Green 2,  Magdalena Szewczyk 2,  Dalia Barsyte-Lovejoy 2 3,  Vijayaratnam Santhakumar 2,  Suzanne Ackloo 2,  Peter Loppnau 2,  Yanjun Li 2,  Almagul Seitova 2,  Taira Kiyota 1,  Jue George Wang 1,  Gilbert G Privé 4,  Douglas A Kuntz 4,  Bhashant Patel 5,  Vaibhavi Rathod 5,  Anand Vala 5,  Bhimsen Rout 5,  Ahmed Aman 1 6,  Gennady Poda 1 6,  David Uehling 1,  Jailall Ramnauth 1,  Levon Halabelian 2 3,  Richard Marcellus 1,  Rima Al-Awar 7 8 9,  Masoud Vedadi 10 11
Affiliations

Affiliations

  • 1 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
  • 3 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
  • 4 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 5 Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Ahmedabad, Gujarat, India.
  • 6 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
  • 7 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada. ralawar@oicr.on.ca.
  • 8 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. ralawar@oicr.on.ca.
  • 9 Department of Chemistry, University of Toronto, Toronto, ON, Canada. ralawar@oicr.on.ca.
  • 10 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada. mvedadi@oicr.on.ca.
  • 11 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. mvedadi@oicr.on.ca.
  • # Contributed equally.
PMID: 39580491 DOI: 10.1038/s41467-024-54500-x
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.

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