1. Structure of the p53 degradation complex from HPV16
- Author
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John C. K. Wang, Hannah T. Baddock, Amirhossein Mafi, Ian T. Foe, Matthew Bratkowski, Ting-Yu Lin, Zena D. Jensvold, Magdalena Preciado López, David Stokoe, Dan Eaton, Qi Hao, and Aaron H. Nile
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Science - Abstract
Abstract Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3-ligase E6AP, also known as UBE3A, to promote degradation of the tumor suppressor, p53. In this study, we present a single-particle cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53, determined at a resolution of ~3.3 Å. Our structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. These findings shed light on the molecular basis of the ternary complex, which has been pursued as a potential therapeutic target for HPV-driven cervical, anal, and oropharyngeal cancers over the last two decades. Understanding the structural and mechanistic underpinnings of this complex is crucial for developing effective therapies to combat HPV-induced cancers. Our findings may help to explain why previous attempts to disrupt this complex have failed to generate therapeutic modalities and suggest that current strategies should be reevaluated.
- Published
- 2024
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