8BB5
Structure of human WDR5 and pVHL:ElonginC:ElonginB bound to PROTAC with Aryl linker
Summary for 8BB5
| Entry DOI | 10.2210/pdb8bb5/pdb |
| Related | 7q2j |
| Descriptor | Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (9 entities in total) |
| Functional Keywords | e3-ligase, wdr5, vhl, elongin, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 78719.68 |
| Authors | Kraemer, A.,Doelle, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2022-10-12, release date: 2022-11-09, Last modification date: 2024-01-31) |
| Primary citation | Schwalm, M.P.,Kramer, A.,Dolle, A.,Weckesser, J.,Yu, X.,Jin, J.,Saxena, K.,Knapp, S. Tracking the PROTAC degradation pathway in living cells highlights the importance of ternary complex measurement for PROTAC optimization. Cell Chem Biol, 30:753-765.e8, 2023 Cited by PubMed Abstract: The multi-step degradation process of PROteolysis TArgeting Chimeras (PROTACs) poses a challenge for their rational development, as the rate-limiting steps that determine PROTACs efficiency remain largely unknown. Moreover, the slow throughput of currently used endpoint assays does not allow the comprehensive analysis of larger series of PROTACs. Here, we developed cell-based assays using the NanoLuciferase and HaloTag that allow measuring PROTAC-induced degradation and ternary complex formation kinetics and stability in cells. Using PROTACs developed for the degradation of WD40 repeat domain protein 5 (WDR5), the characterization of the mode of action of these PROTACs in the early degradation cascade revealed a key role of ternary complex formation and stability. Comparing a series of ternary complex crystal structures highlighted the importance of an efficient E3-target interface for ternary complex stability. The developed assays outline a strategy for the rational optimization of PROTACs using a series of live cell assays monitoring key steps of the early PROTAC-induced degradation pathway. PubMed: 37354907DOI: 10.1016/j.chembiol.2023.06.002 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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