Structure of the p53 degradation complex from HPV16

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 ()
Additional contact information
John C. K. Wang: Calico Life Sciences LLC
Hannah T. Baddock: Calico Life Sciences LLC
Amirhossein Mafi: Calico Life Sciences LLC
Ian T. Foe: Calico Life Sciences LLC
Matthew Bratkowski: Calico Life Sciences LLC
Ting-Yu Lin: Calico Life Sciences LLC
Zena D. Jensvold: Calico Life Sciences LLC
Magdalena Preciado López: Calico Life Sciences LLC
David Stokoe: Calico Life Sciences LLC
Dan Eaton: Calico Life Sciences LLC
Qi Hao: Calico Life Sciences LLC
Aaron H. Nile: Calico Life Sciences LLC

Nature Communications, 2024, vol. 15, issue 1, 1-18

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.

Date: 2024
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DOI: 10.1038/s41467-024-45920-w

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