Enhanced dynamic coupling in a nuclear receptor underlies ligand activity.

Abstract

Bile acids are signaling molecules with critical roles in cholesterol and lipid metabolism, achieved by regulating the transcriptional activity of the farnesoid X receptor (FXR, NR1H4), otherwise known as the bile acid receptor. Modifications to the C6 position of the steroidal core yield bile acid derivatives with 100x improved potency over endogenous bile acids. Prevailing hypotheses suggested increased binding affinity for FXR as the driver for this activity enhancement. Our experimental results contradict this suggestion, motivating us to investigate the underlying mechanisms of enhanced ligand activity. We combined functional assays with over 200 microseconds of simulations, revealing an unexpected role for helix 5 in the allosteric signaling of obeticholic acid (OCA). We uncovered dynamic coupling between adjacent helices 5 and 7, which is uniquely enhanced by the bile acid modification. Ultimately, the enhanced potency of the bile acid analog can be traced to its effect on FXR dynamics. In addition to identifying a previously unknown mechanistic role for helix 5-helix 7 coupling in FXR, these results emphasize the inextricable linkage between the activity of nuclear receptor ligands and their effects on receptor dynamics.