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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.

Author information

1
Department of Physical Chemistry and Institute of Biotechnology, University of Granada, 18071, Granada, Spain.
2
Instituto de Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, C/Serrano 119, 28006, Madrid, Spain.
3
Institute for Advanced Biosciences, Structural Biology of Novel Targets in Human Diseases Group, Inserm U1209-CNRS 5309-Université Grenoble-Alpes, 38700, La Tronche, France.
4
Donnelly Centre for Cellular and Biomolecular Research, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
5
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST). Baldiri Reixac, 10, Barcelona, 08028, Spain.
6
Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160, Derio, Spain.
7
IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013, Bilbao, Spain.
8
ICREA, Passeig Lluís Companys 23, 08010, Barcelona, Spain.
9
Department of Physical Chemistry and Institute of Biotechnology, University of Granada, 18071, Granada, Spain. iluque@ugr.es.

Abstract

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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