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

Here, we report the structural and functional basis by which the viral oncoprotein E7 hijacks host CRL2ZER1 to degrade retinoblastoma protein (Rb) and drive E2F-dependent proliferation. Crystal structures reveal that the N-terminal MH/N-degron of E7 engages a defined pocket within the 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.