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

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 su...

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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2024-11-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-024-54500-x
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Summary: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.
ISSN:2041-1723

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