ELiAH2: update of the atlas of E3 ligases in human tissues by integrating tissue-specificity and docking properties of ligands for targeted protein degradation

Abstract

Targeted protein degradation (TPD), including proteolysis-targeting chimeras (PROTACs), requires coordinated selection of E3 ligases, target proteins, and ligands to achieve efficient and tissue-selective degradation. However, current TPD resources provide limited support for integrating tissue-specific transcriptomic evidence with structural compatibility during early candidate prioritization. Here, we present ELiAH2, an expanded database for transcriptome- and structure-guided prioritization of TPD candidates. ELiAH2 integrates GTEx RNA-seq profiles across 24 human tissues to characterize tissue-specific expression patterns of E3 ligases and target genes. Compared with the previous version, ELiAH, current update presented over 200% of expansion for the number of covered tissues and samples. Previously, E3 ligase-target gene associations were inferred using mutual information-based network analysis, enabling users to explore transcriptomic relationships. To further support structural evaluation, ELiAH2 provides large-scale docking datasets comprising 827,385 E3 ligase-target protein pairs and 7,800,521 protein-ligand docking models, including E3 ligase-ligand and target protein-ligand interactions. Docking scores, ranked interaction tables, gene and ligand identifiers, and downloadable PDB structures are incorporated into the web interface. By combining tissue specificity, E3-target association, protein-protein docking, and protein-ligand docking, ELiAH2 provides a comprehensive resource for narrowing the TPD search space and supporting rational degrader design. ELiAH2 is freely available at https://eliahdb.org.