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

• Published in: Nature communications 2024-11, Vol.15 (1), p.10165-17, Article 10165
• Main Authors: Mabanglo, Mark F., Wilson, Brian, Noureldin, Mahmoud, Kimani, Serah W., Mamai, Ahmed, Krausser, Chiara, González-Álvarez, Héctor, Srivastava, Smriti, Mohammed, Mohammed, Hoffer, Laurent, Chan, Manuel, Avrumutsoae, Jamie, Li, Alice Shi Ming, Hajian, Taraneh, Tucker, Sarah, Green, Stuart, Szewczyk, Magdalena, Barsyte-Lovejoy, Dalia, Santhakumar, Vijayaratnam, Ackloo, Suzanne, Loppnau, Peter, Li, Yanjun, Seitova, Almagul, Kiyota, Taira, Wang, Jue George, Privé, Gilbert G., Kuntz, Douglas A., Patel, Bhashant, Rathod, Vaibhavi, Vala, Anand, Rout, Bhimsen, Aman, Ahmed, Poda, Gennady, Uehling, David, Ramnauth, Jailall, Halabelian, Levon, Marcellus, Richard, Al-awar, Rima, Vedadi, Masoud
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 631/535/1266; 631/57/2272/1590; 631/92/613; 82/103; 82/16; 82/80; 82/83; Cancer; Cancer research; Chimeras; Crystal structure; Crystallography, X-Ray; Degradation; Down-regulation; HEK293 Cells; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Ligands; Medical research; Models, Molecular; multidisciplinary; Protein Binding; Proteins; Proteolysis; Receptors; Science; Science (multidisciplinary); Substrate Specificity; Substrates; Therapeutic targets; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54500-x

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. The authors show that DCAF1, a substrate receptor of CUL4 and EDVP E3 ligases, can be recruited by PROTACs to degrade the cancer drug target, WDR5. They also report the crystal structures of PROTAC ternary complexes that reveal a significant role for loops in DCAF1 substrate recognition, a potential mechanism behind the diverse substrate specificity of DCAF1.