Binding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4 Iglesias-Bexiga, Manuel Palencia, Andrés The recognition of PPxY viral Late domains by the third WW domain of the HECT-E3 ubiquitin ligase NEDD4 (hNEDD4-WW3) is essential for the completion of the budding process of numerous enveloped viruses, including Ebola, Marburg, HTLV1 or Rabies. hNEDD4-WW3 has been validated as a promising target for the development of novel host-oriented broad spectrum antivirals. Nonetheless, finding inhibitors with good properties as therapeutic agents remains a challenge since the key determinants of binding affinity and specificity are still poorly understood. We present here a detailed structural and thermodynamic study of the interactions of hNEDD4-WW3 with viral Late domains combining isothermal titration calorimetry, NMR structural determination and molecular dynamics simulations. Structural and energetic differences in Late domain recognition reveal a highly plastic hNEDD4-WW3 binding site that can accommodate PPxY-containing ligands with varying orientations. These orientations are mostly determined by specific conformations adopted by residues I859 and T866. Our results suggest a conformational selection mechanism, extensive to other WW domains, and highlight the functional relevance of hNEDD4-WW3 domain conformational flexibility at the binding interface, which emerges as a key element to consider in the search for potent and selective inhibitors of therapeutic interest. 2019-11-04T10:03:52Z 2019-11-04T10:03:52Z 2019 info:eu-repo/semantics/article Iglesias-Bexiga, M., Palencia, A., Corbi-Verge, C., Martin-Malpartida, P., Blanco, F. J., Macias, M. J., ... & Luque, I. (2019). Binding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4. Scientific reports, 9(1), 1-17. http://hdl.handle.net/10481/57666 10.1038/s41598-019-50701-3 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Atribución 3.0 España Springer Nature