Structural modeling supports an interaction between the Drosophila Estrogen-Related Receptor and Sima/HIF1α

The Drosophila Estrogen-Related Receptor (dERR) is an orphan nuclear receptor that regulates developmental metabolism, yet the protein cofactors that modulate its activity remain poorly defined. Here, we used the AI-based FlyPredictome platform to identify candidate dERR interaction partners and evaluate their predicted structural interfaces. Among the highest-confidence interactors is the transcription factor Sima, which represents the Drosophila ortholog of HIF1α - an interaction that was reciprocally identified in both dERR and Sima/HIF1α interaction datasets. Structural modeling predicted binding between the dERR ligand-binding domain and a conserved LXXLL motif in Sima/HIF1α. Notably, the predicted dERR- Sima/HIF1α interaction interface includes residues previously shown to be essential for in vitro binding, providing independent structural support for this biologically relevant protein-protein interaction.