4q0a
From Proteopedia
Vitamin D Receptor complex with lithocholic acid
Structural highlights
FunctionVDRA_DANRE Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.[1] Publication Abstract from PubMedThe vitamin D receptor (VDR), an endocrine nuclear receptor for 1alpha,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. Structural insights into the molecular mechanism of vitamin d receptor activation by lithocholic Acid involving a new mode of ligand recognition.,Belorusova AY, Eberhardt J, Potier N, Stote RH, Dejaegere A, Rochel N J Med Chem. 2014 Jun 12;57(11):4710-9. doi: 10.1021/jm5002524. Epub 2014 May 21. PMID:24818857[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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