1 research outputs found
Structural Insights into the Molecular Mechanism of Vitamin D Receptor Activation by Lithocholic Acid Involving a New Mode of Ligand Recognition
The
vitamin D receptor (VDR), an endocrine nuclear receptor for
1Ī±,25-dihydroxyvitamin D3, acts also as a bile acid sensor by
binding lithocholic acid (LCA). The crystal structure of the zebrafish
VDR ligand binding domain in complex with LCA and the SRC-2 coactivator
peptide reveals the binding of two LCA molecules by VDR. One LCA binds
to the canonical ligand-binding pocket, and the second one, which
is not fully buried, is anchored to a site located on the VDR surface.
Despite the low affinity of the alternative site, the binding of the
second molecule promotes stabilization of the active receptor conformation.
Biological activity assays, structural analysis, and molecular dynamics
simulations indicate that the recognition of two ligand molecules
is crucial for VDR agonism by LCA. The unique binding mode of LCA
provides clues for the development of new chemical compounds that
target alternative binding sites for therapeutic applications