Understanding an E3 ligase is an essential step for choosing a target for screening in the case of a molecular glue, or in the chemical design of a PROTAC, as this key mechanism determines whether ubiquitination and degradation takes place when creating a degrader, or in the creation of k63 chains in the case of stabilization. Dutta et al 2025. Nature Communications (2025) paper tackles a long-standing problem in the ubiquitin field: while hundreds of human E3 ligases are known, they are typically classified using coarse, mechanism-based labels (RING, HECT, RBR) that fail to capture their true biological and functional diversity. The authors assemble a high-confidence, curated human E3 ligome and apply a multi-scale classification framework that integrates sequence similarity, domain composition, predicted structure, and functional annotations. Rather than forcing E3s into rigid categories, this approach creates a hierarchical map that reflects both shared evolutionary features and subtle mechanistic differences. Understanding the structure of E3 ligase families for discovering novel drugs.
A key advance is the use of machine-learning–derived distance metrics to identify relationships between E3 ligases that are not obvious from sequence alone. This reveals previously unappreciated subfamilies and functional groupings, including atypical E3s and ligases with hybrid or context-dependent mechanisms. The resulting classification links E3 clusters to biological processes, substrate preferences, and interaction networks, helping explain why certain E3s behave similarly in cells despite belonging to different canonical classes and discover new drugs.
From a drug discovery perspective, the work provides a much-needed roadmap for E3 ligase targeting. By organizing the E3 ligome according to structural and functional similarity, the framework highlights underexplored E3 families, suggests which ligases may share ligandability or recruiter compatibility, and helps rationalize why certain E3s (like CRBN or VHL) have been more tractable for small-molecule modulation. This is particularly valuable for PROTAC and molecular glue discovery, where selecting new E3 ligases is a major bottleneck.
Further reading about E3 ligases and the assays used for discovering them here.
The full paper is available here.
Understanding an E3 ligase is an essential step for choosing a target for screening in the case of a molecular
With ubiquitin’s core functions in plants and animals being so similar it has long been speculated that insights into the
The functional consequences of protein polyubiquitination are determined by the type of ubiquitin chain assembled on the substrate. Among the
While direct K-RAS inhibitors represent a major therapeutic advance, targeting this oncoprotein remains a significant challenge due to limited druggable
Pan-selective Tandem Ubiquitin-Binding Entities (TUBEs) are engineered, high-affinity reagents composed of multiple ubiquitin-associated (UBA) domains that bind polyubiquitin chains with
LifeSensors is pleased to bring attention to some of our academic colleagues who have used our products in the past
Understanding an E3 ligase is an essential step for choosing a target for screening in the case of a molecular
With ubiquitin’s core functions in plants and animals being so similar it has long been speculated that insights into the
The functional consequences of protein polyubiquitination are determined by the type of ubiquitin chain assembled on the substrate. Among the
While direct K-RAS inhibitors represent a major therapeutic advance, targeting this oncoprotein remains a significant challenge due to limited druggable
Pan-selective Tandem Ubiquitin-Binding Entities (TUBEs) are engineered, high-affinity reagents composed of multiple ubiquitin-associated (UBA) domains that bind polyubiquitin chains with
LifeSensors is pleased to bring attention to some of our academic colleagues who have used our products in the past
