@misc{10481/99958,
year = {2019},
month = {10},
url = {https://hdl.handle.net/10481/99958},
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.},
organization = {This research has been financed by grants BIO2009-13261-C02, BIO2012-39922-CO2 and BIO2016-78746-C2-1-R from the Spanish Ministry of Education and Science (I.L.) including AEI/FEDER EU funds, by CTQ2017-83810-R grant (F.J.B) and by BFU2014-53787-P, the IRB Barcelona and the BBVA Foundation (M.J.M). M.I.B. was a recipient of a research contract from the Spanish Ministry of Education and Science. M.J.M is an ICREA Programme Investigator.},
publisher = {Editor Nature Publishing Group UK},
keywords = {Viral Late domains},
keywords = {Human NEDD4-WW3 domain},
keywords = {Binding interface},
keywords = {Conformational flexibility},
title = {Binding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4},
doi = {https://doi.org/10.1038/s41598-019-50701-3},
author = {Iglesias Bexiga, Manuel and Palencia, Andrés and Corbi Verge, Carles and Martín-Malpartida, Pau and Blanco, Francisco J. and Macías, María J. and Sánchez Cobos, Eva María and Luque Fernández, Irene},
}