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 100× 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 μs of simulations, revealing an unexpected role for helix 5 in the allosteric signaling of obeticholic acid. We uncovered dynamic coupling b

SUBMITTER: Yu T 

PROVIDER: S-EPMC11783427 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature