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A chimeric protein was built by fusing a PDZ domain and an LxxLL motif, both known to bind E6. NMR spectroscopy, calorimetry and a mammalian protein complementation assay converged to show that the resulting PDZ\u2010LxxLL chimera is a bivalent nanomolar ligand of E6, while its separated PDZ and LxxLL components are only micromolar binders. The chimera binds to all of the hrm\u2010HPV E6\u2005proteins tested but not to low\u2010risk mucosal or cutaneous HPV\u2005E6. Adenovirus\u2010mediated expression of the chimera specifically induces the death of HPV\u2010positive cells, concomitant with increased levels of the tumour suppressor P53, its transcriptional target p21, and the apoptosis marker cleaved caspase\u20053. 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