ArticleScientific reports2019
Binding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 19 citations in OpenAlex.
- Selective Autophagy Mediated by Protein Ubiquitination in Major Prevalent Zoonoses.Transboundary and emerging diseases · 2025Review
- Exploring the druggability of the UEV domain of human TSG101 in search for broad-spectrum antivirals.Protein science : a publication of the Protein Society · 2025Article
- A quantitative intracellular peptide binding assay reveals recognition determinants and context dependence of short linear motifs.bioRxiv : the preprint server for biology · 2024Article
- Identification of Prospective Ebola Virus VP35 and VP40 Protein Inhibitors from Myxobacterial Natural Products.Biomolecules · 2024Article
- The multifaceted interactions between pathogens and host ESCRT machinery.PLoS pathogens · 2023Review
- Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs.Nature communications · 2023Article
- Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors.International journal of molecular sciences · 2023Article
- Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins.Viruses · 2021Review
- Compound FC-10696 Inhibits Egress of Marburg Virus.Antimicrobial agents and chemotherapy · 2021Article
- Molecular Interactions between Two LMP2A PY Motifs of EBV and WW Domains of E3 Ubiquitin Ligase AIP4.Life (Basel, Switzerland) · 2021Article
- Structural and Biophysical Insights into the Function of the Intrinsically Disordered Myc Oncoprotein.Cells · 2020Review
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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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