9BA2
Crystal structure of the binary complex of DCAF1 and WDR5
Summary for 9BA2
| Entry DOI | 10.2210/pdb9ba2/pdb |
| Descriptor | DDB1- and CUL4-associated factor 1, WD repeat-containing protein 5, IMIDAZOLE, ... (4 entities in total) |
| Functional Keywords | e3 ligase, adaptor, protac, wdr, ternary complex, protein binding |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 74801.11 |
| Authors | Mabanglo, M.F.,Wilson, B.J.,Srivastava, S.,Al-awar, R.,Vedadi, M. (deposition date: 2024-04-03, release date: 2024-11-06, Last modification date: 2024-12-04) |
| Primary citation | Mabanglo, M.F.,Wilson, B.,Noureldin, M.,Kimani, S.W.,Mamai, A.,Krausser, C.,Gonzalez-Alvarez, H.,Srivastava, S.,Mohammed, M.,Hoffer, L.,Chan, M.,Avrumutsoae, J.,Li, A.S.M.,Hajian, T.,Tucker, S.,Green, S.,Szewczyk, M.,Barsyte-Lovejoy, D.,Santhakumar, V.,Ackloo, S.,Loppnau, P.,Li, Y.,Seitova, A.,Kiyota, T.,Wang, J.G.,Prive, G.G.,Kuntz, D.A.,Patel, B.,Rathod, V.,Vala, A.,Rout, B.,Aman, A.,Poda, G.,Uehling, D.,Ramnauth, J.,Halabelian, L.,Marcellus, R.,Al-Awar, R.,Vedadi, M. Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity. Nat Commun, 15:10165-10165, 2024 Cited by PubMed 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. PubMed: 39580491DOI: 10.1038/s41467-024-54500-x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.97 Å) |
Structure validation
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