Structural basis for HPV16-specific hijacking of the CRL2ZER1 ubiquitin ligase

Human papillomavirus (HPV) 16 accounts for the majority of HPV-associated cervical and oropharyngeal cancers, yet the structural basis of its uniquely potent hijacking of host ubiquitin ligases remains unclear. Here we present cryo-EM structures of HPV16 E7 in association with the CRL2ZER1 E3 ligase (CRL2ZER1/E7 complex) and the CRL2ZER1/E7/RB complex, revealing an elongated yet dynamic assembly in which CUL2 undergoes conformational transitions that couple substrate recruitment to ubiquitination. ZER1 adopts a distinctive serpentine fold, and HPV16 E7 engages it through a composite pocket-groove interface. Although E7 preserves canonical N-degron–like backbone contacts, it additionally exploits a methionine-specific hydrophobic sub-pocket and an extended ARM-groove surface to achieve stable recruitment. Molecular dynamics and UVPD analyses further show that HPV16 E7 possesses unusually high N-terminal accessibility, in contrast to other high-risk variants and the E80A/D81A loss-of-function mutant, providing a type-specific mechanism for accessing the ZER1 pocket. These findings define the structural and dynamic basis of HPV16-specific CRL2ZER1 hijacking and suggest new opportunities for precision therapeutic targeting of HPV16-driven cancers.