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The human papillomavirus (HPV) E6 protein plays an important role in the development of cancer associated with certain high risk strains. In addition to binding to p53, E6 also binds to the PDZ domain of several proteins that participate in cell adherence and polarity. The mechanism by which E6 interacts with PDZ is not well understood, but in this Paper of the Week, Celestine Chi and colleagues employed multiple biophysical techniques to explore E6 binding to the PDZ domains of the tumor suppressor protein SAP97; they developed various constructs that consisted of one, two, or all three PDZ domains. They found that PDZ binding is not mutually exclusive, as all three domains can simultaneously bind to E6. Intriguingly, the quaternary complex had the same apparent hydrodynamic volume as ligand-free PDZ123, suggesting that a conformational change occurs upon PDZ-E6 binding that compacts the complex. Using NMR, Chi and colleagues also identified a subset of residues distal to the canonical binding pocket in PDZ2 domain that were involved in interacting with E6, suggesting that a larger proportion of the protein surface defines binding specificity than previously reported. This study not only provides new clues about how papillomavirus alters cellular function so as to induce cancer but also explores mechanistic aspects to understand these results on the conformational level.