ArticleMolecular biology and evolution2026
Evolutionary remodeling of the FXR binding pocket drove functional divergence and ligand discrimination.
Article in Molecular biology and evolution, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Nuclear receptor subfamilies are comprised of members that can have markedly different ligand preferences. The NR1H subfamily contains the farnesoid X receptor (FXR) and liver X receptors (LXR), which regulate myriad metabolic processes, often in a coordinated fashion. As sensors for bile acids and oxysterols, respectively, it is not known what ligand(s) activated the precursor of FXR and LXR. We reconstruct the common FXR/LXR vertebrate ancestor and determine that it responds to neither class of ligands for the extant receptors. Using structural and functional analysis, we identify the set of evolutionary substitutions that recapitulate the shift in ligand preference from the FXR/LXR ancestor to the ancestral vertebrate FXR. We show that the substitutions reshaped the ligand binding pocket to drive this functional shift. Subsequent evolutionary mutations altered the secondary structure of FXR to scaffold the binding pocket and support functional specialization.
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