A 16-mer peptide library was screened using the yeast two-hybrid system to identify peptides which specifically interact with the human papillomavirus type 16 (HPV-16) E6 protein. Four different peptides were identified, three of which contained an E-L-L/V-G motif. A fifth E6 binding peptide, derived from the putative tumour suppressor protein tuberin, was identified during a two-hybrid screen of a HeLa cDNA expression library. This peptide contained a D-I-L-G motif. Homology to the peptides was found within the E6 binding proteins E6-AP and E6-BP. A synthetic peptide containing the ELLG motif blocked the interaction of E6 with both E6-AP and E6-BP. The data suggest that E6 interacts through a structurally similar binding domain present within a number of cellular proteins.