Unique protein dynamics distinguish the highly homologous LXR α and β isotypes

The liver X receptor (LXR) is expressed as α and β subtypes (NR1H3/NR1H2), which play both separate and overlapping roles in cholesterol metabolism. As ligand-regulated transcription factors, LXRα and LXRβ are activated by oxysterol. The two isoforms have high percent identity, sharing nearly identical structures and binding pockets. With these similarities, it is not clear how ligands distinguish between LXRα and LXRβ binding pockets. Yet, the ability to design isoform-specific modulator is highly dependent on this knowledge. Here, we test the hypothesis that, despite high structural similarity, the dynamic behavior of the receptors is distinct and can reveal fundamental differences between the isoforms. Using molecular dynamics simulations on a library of 27 oxysterols, we compare dynamic contacts, fluctuations and allosteric signaling in the ligand binding domains of both receptors. We quickly identify stability differences linked to subtle changes in secondary structure and inter-residue contacts. Using our reconstructed sequence of ancestral vertebrate LXR, we reveal that both receptors inherited distinct structural and/or dynamical features of the ancestor which underlie their dynamic differences.