6ZHC

PROTAC6 mediated complex of VHL:EloB:EloC and Bcl-xL

This is a non-PDB format compatible entry.

Summary for 6ZHC

• Entry DOI: 10.2210/pdb6zhc/pdb
• Descriptor: von Hippel-Lindau disease tumor suppressor, Elongin-B, Elongin-C, ... (9 entities in total)
• Functional Keywords: protac complex, targeted degradation, ubiquitin ligase, bifunctional ligand, e3 ligase, bcl-xl, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 70560.51

Authors

Chung, C. (deposition date: 2020-06-22, release date: 2020-08-05, Last modification date: 2024-01-24)

Primary citation

Chung, C.W.,Dai, H.,Fernandez, E.,Tinworth, C.P.,Churcher, I.,Cryan, J.,Denyer, J.,Harling, J.D.,Konopacka, A.,Queisser, M.A.,Tame, C.J.,Watt, G.,Jiang, F.,Qian, D.,Benowitz, A.B.
Structural Insights into PROTAC-Mediated Degradation of Bcl-xL.
Acs Chem.Biol., 15:2316-2323, 2020

PubMed Abstract: The Bcl-2 family of proteins, such as Bcl-xL and Bcl-2, play key roles in cancer cell survival. Structural studies of Bcl-xL formed the foundation for the development of the first Bcl-2 family inhibitors and FDA approved drugs. Recently, teolysis rgeting himeras (PROTACs) that degrade Bcl-xL have been proposed as a therapeutic modality with the potential to enhance potency and reduce toxicity versus antagonists. However, no ternary complex structures of Bcl-xL with a PROTAC and an E3 ligase have been successfully determined to guide this approach. Herein, we report the design, characterization, and X-ray structure of a VHL E3 ligase-recruiting Bcl-xL PROTAC degrader. The 1.9 Å heterotetrameric structure, composed of (ElonginB:ElonginC:VHL):PROTAC:Bcl-xL, reveals an extensive network of neo-interactions, between the E3 ligase and the target protein, and between noncognate parts of the PROTAC and partner proteins. This work illustrates the challenges associated with the rational design of bifunctional molecules where interactions involve composite interfaces.

PubMed: 32697072
DOI: 10.1021/acschembio.0c00266

Experimental method

X-RAY DIFFRACTION (1.92 Å)