@misc{10481/57666,
year = {2019},
url = {http://hdl.handle.net/10481/57666},
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).},
publisher = {Springer Nature},
title = {Binding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4},
doi = {10.1038/s41598-019-50701-3},
author = {Iglesias-Bexiga, Manuel and Palencia, Andrés},
}