On Mar. 23, 2026, The Walter and Eliza Hall Institute of Medical Research (WEHI) researchers have led a major global effort to create the first authoritative atlas for a class of enzymes that regulate almost every cellular process in the human body. Published in Cell, the breakthrough study establishes the first gold-standard reference for all human E3 ligases, resolving nearly two decades of inconsistencies within the field. The atlas will enable researchers to study E3 ligases in unprecedented detail, paving the way for the development of enhanced therapies for diseases linked.

E3 ligases are enzymes that control the fate and function of proteins in virtually every cellular process. These enzymes act as cellular ‘gatekeepers’, deciding which proteins should be activated, silenced and destroyed. They do this by attaching a small molecule called ubiquitin onto proteins to ‘tag’ them, helping the cell control what proteins do and whether they are repaired, relocated, or destroyed. Errors in these control systems can sometimes lead to an accumulation of old or damaged proteins, which can trigger a broad range of diseases.

Despite decades of being linked to human health, there are disparities about how the scientific community defines E3 ligases – making it challenging to build a coherent understanding of how these enzymes function in health and disease. The new atlas, known as the human E3ome, is a landmark unified classification framework that changes this.

In the four-year study, WEHI researchers along with worldwide specialists collated more than 1100 historically proposed E3 genes, reviewing domain structural features, protein domains and interaction data to evaluate the evidence supporting each candidate. Of these, 672 met the highest confidence criteria. Previous estimates about the number of existing E3 ligases widely varied – with published research ranging from approximately 300 to over 1000. The study builds on foundational research conducted in 2008 by researchers at The Scripps Research Institute, who became the first to develop the human E3 ligase annotation.

While the E3-ome is a pioneering resource, researchers emphasise the 672 enzymes currently defined is not a static number. This figure is expected to grow as new structural, biochemical and genetic data become available. To support ongoing discovery, researchers have made the complete E3 ligase compendium publicly available, enabling other researchers to build on the classification and functional insights.