Molecular basis of the HPV E7-ZER1 axis reveals a ligandable vulnerability in HPV-positive cancers

Persistent infection with high-risk human papillomaviruses (HPVs), notably HPV-16 and HPV-18, underlies most cervical cancers and many head and neck cancers. Here, we report the structural and functional basis by which the viral oncoprotein E7 hijacks host CRL2^ZER1 to degrade retinoblastoma (Rb) protein and drive E2F-dependent proliferation. Crystal structures reveal that the N-terminal MH/N-degron of E7 engages a defined pocket within the armadillo (ARM)-repeat domain of ZER1. Disruption of this interface abolishes E7-ZER1 binding, prevents Rb degradation, silences E2F transcriptional programs, and impairs proliferation of HPV-positive cancer cells. Guided by these insights, we identify a first-in-class small-molecule inhibitor that blocks E7-ZER1 association, restores Rb stability, and selectively suppresses HPV-positive tumor growth in vivo. These results define a viral mimicry mechanism and nominate the ZER1 degron pocket as a ligandable therapeutic target for HPV-driven malignancies, highlighting translational opportunities for targeted therapy.