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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Binding Sites
  • Databases, Protein
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Molecular Dynamics Simulation
  • Nedd4 Ubiquitin Protein Ligases / chemistry*
  • Nedd4 Ubiquitin Protein Ligases / metabolism*
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Binding
  • Protein Domains
  • Thermodynamics
  • Viral Proteins / chemistry*


  • Ligands
  • Peptides
  • Viral Proteins
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human