| Autor: |
Wang, John C. K., Baddock, Hannah T., Mafi, Amirhossein, Foe, Ian T., Bratkowski, Matthew, Lin, Ting-Yu, Jensvold, Zena D., Preciado López, Magdalena, Stokoe, David, Eaton, Dan, Hao, Qi, Nile, Aaron H. |
| Zdroj: |
Nature Communications; 1/2/2024, Vol. 15 Issue 1, p1-18, 18p |
| Abstrakt: |
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.HPV’s E6 protein promotes cancer by degrading p53. This study reveals the cryoEM structure of HPV16 E6 in complex with E6AP and p53, highlighting their picomolar affinity and large protein-protein interaction interface. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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