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Sci Rep. 2019 Oct 21;9(1):15076. doi: 10.1038/s41598-019-50701-3.

Binding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4.

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Department of Physical Chemistry and Institute of Biotechnology, University of Granada, 18071, Granada, Spain.
Instituto de Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, C/Serrano 119, 28006, Madrid, Spain.
Institute for Advanced Biosciences, Structural Biology of Novel Targets in Human Diseases Group, Inserm U1209-CNRS 5309-Université Grenoble-Alpes, 38700, La Tronche, France.
Donnelly Centre for Cellular and Biomolecular Research, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona, 08028, Spain.
Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160, Derio, Spain.
IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013, Bilbao, Spain.
ICREA, Passeig Lluís Companys 23, 08010, Barcelona, Spain.
Department of Physical Chemistry and Institute of Biotechnology, University of Granada, 18071, Granada, Spain.


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.

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