Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 11, Pages 4710-4719Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm5002524
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Funding
- Fondation pour la Recherche Medicale (FRM)
- Agence Nationale de Recherche [ANR-13-BSV8-0024-01]
- Centre National de la Recherche Scientifique (CNRS)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Universite de Strasbourg (UDS)
- Instruct part of the European Strategy Forum on Research Infrastructures (ESFRI)
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01]
- French Ministry of Education and Research
- project EQUIP@MESO
- Agence Nationale de la Recherche (ANR) [ANR-13-BSV8-0024] Funding Source: Agence Nationale de la Recherche (ANR)
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The vitamin D receptor (VDR), an endocrine nuclear receptor for 1 alpha,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.
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