8FY2
E3:PROTAC:target ternary complex structure (VCB/WH244/BCL-2)
Summary for 8FY2
| Entry DOI | 10.2210/pdb8fy2/pdb |
| Descriptor | von Hippel-Lindau disease tumor suppressor, Elongin-B, Elongin-C, ... (5 entities in total) |
| Functional Keywords | ternary complex, degrader, transcription |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 69420.14 |
| Authors | |
| Primary citation | Nayak, D.,Lv, D.,Yuan, Y.,Zhang, P.,Hu, W.,Nayak, A.,Ruben, E.A.,Lv, Z.,Sung, P.,Hromas, R.,Zheng, G.,Zhou, D.,Olsen, S.K. Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL. Nat Commun, 15:2743-2743, 2024 Cited by PubMed Abstract: Overexpression of BCL-xL and BCL-2 play key roles in tumorigenesis and cancer drug resistance. Advances in PROTAC technology facilitated recent development of the first BCL-xL/BCL-2 dual degrader, 753b, a VHL-based degrader with improved potency and reduced toxicity compared to previous small molecule inhibitors. Here, we determine crystal structures of VHL/753b/BCL-xL and VHL/753b/BCL-2 ternary complexes. The two ternary complexes exhibit markedly different architectures that are accompanied by distinct networks of interactions at the VHL/753b-linker/target interfaces. The importance of these interfacial contacts is validated via functional analysis and informed subsequent rational and structure-guided design focused on the 753b linker and BCL-2/BCL-xL warhead. This results in the design of a degrader, WH244, with enhanced potency to degrade BCL-xL/BCL-2 in cells. Using biophysical assays followed by in cell activities, we are able to explain the enhanced target degradation of BCL-xL/BCL-2 in cells. Most PROTACs are empirically designed and lack structural studies, making it challenging to understand their modes of action and specificity. Our work presents a streamlined approach that combines rational design and structure-based insights backed with cell-based studies to develop effective PROTAC-based cancer therapeutics. PubMed: 38548768DOI: 10.1038/s41467-024-46922-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.98 Å) |
Structure validation
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