This study presents the cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53 at a resolution of ~3.3 Å. The structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. The findings provide insights into the molecular basis of the ternary complex, which has been a potential therapeutic target for HPV-driven cancers. The study also includes mutagenesis and ubiquitination assays, as well as molecular dynamics simulations, to validate the interactions and their functional significance. The results suggest that previous attempts to disrupt the complex have failed due to the high-affinity binding and the dynamic nature of certain regions. The study concludes by discussing the implications for therapeutic development and the need to reevaluate current strategies.This study presents the cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53 at a resolution of ~3.3 Å. The structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. The findings provide insights into the molecular basis of the ternary complex, which has been a potential therapeutic target for HPV-driven cancers. The study also includes mutagenesis and ubiquitination assays, as well as molecular dynamics simulations, to validate the interactions and their functional significance. The results suggest that previous attempts to disrupt the complex have failed due to the high-affinity binding and the dynamic nature of certain regions. The study concludes by discussing the implications for therapeutic development and the need to reevaluate current strategies.