ArticleMolecular cell2016
System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes.
Article in Molecular cell, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers.
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Who cites it
104 citing papers in PubMed, 170 citations in OpenAlex.
- HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures.The Journal of biological chemistry · 2026Review
- UBA6 specificity for ubiquitin E2 conjugating enzymes reveals a priority mechanism of BIRC6.Nature structural & molecular biology · 2026Article
- Mesostructured Water Enhances Stability of ProteinMPNN-Designed Ubiquitin-Fold Proteins.Journal of the American Chemical Society · 2026Article
- E2 variants for probing E3 ubiquitin ligase activities.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The role of HECT-type E3 ubiquitin ligases in inflammation.Frontiers in immunology · 2026Review
- Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies.Nature communications · 2025Article
- Structure-based design of potent and selective inhibitors of the HECT ligase NEDD4.Communications chemistry · 2025Article
- Structural basis of ubiquitin ligase Nedd4-2 autoinhibition and regulation by calcium and 14-3-3 proteins.Nature communications · 2025Article
- Suppressing Tymovirus replication in plants using a variant of ubiquitin.PLoS pathogens · 2025Article
- Protein semisynthesis reveals plasticity in HECT E3 ubiquitin ligase mechanisms.Nature chemistry · 2024Article
- Proximal Co-Translation Facilitates Detection of Weak Protein-Protein Interactions.International journal of molecular sciences · 2024Article
- Look for the Scaffold: Multifaceted Regulation of Enzyme Activity by 14-3-3 Proteins.Physiological research · 2024Review
- Machine Learning Models to Interrogate Proteome-Wide Covalent Ligandabilities Directed at Cysteines.JACS Au · 2024Article
- Structural and functional validation of a highly specific Smurf2 inhibitor.Protein science : a publication of the Protein Society · 2024Article
- Machine Learning Models to Interrogate Proteomewide Covalent Ligandabilities Directed at Cysteines.bioRxiv : the preprint server for biology · 2024Article
- WWP1 E3 ligase at the crossroads of health and disease.Cell death & disease · 2023Review
- Bacterial ligases reveal fundamental principles of polyubiquitin specificity.Molecular cell · 2023Article
- What Strengthens Protein-Protein Interactions: Analysis and Applications of Residue Correlation Networks.Journal of molecular biology · 2023Article
- Recognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides.Nature communications · 2023Article
- Time-resolved cryo-EM (TR-EM) analysis of substrate polyubiquitination by the RING E3 anaphase-promoting complex/cyclosome (APC/C).Nature structural & molecular biology · 2023Article
44 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 13 institutions in 3 countries.
Funding
Abstract
HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT-UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.