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Graduate Schools of Medicine (R.A., I.S., M.M.) and Frontier Biosciences (I.S., M.M.), Osaka University, Osaka 565-0871, Japan; Howard Hughes Medical Institute and Department of Pharmacology (A.I.S., D.J.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050; Institute of Biomaterials and Bioengineering and School of Biomedical Science (K.Y., S.Y.), Tokyo Medical and Dental University, Tokyo 101-0062, Japan
Address all correspondence and requests for reprints to: Makoto Makishima, Graduate School of Frontier Biosciences, Osaka University, 2–2 Yamadaoka, H2, Suita, Osaka 565-0871, Japan. E-mail: maxima{at}fbs.osaka-u.ac.jp.
The vitamin D receptor (VDR), initially identified as a nuclear receptor for 1
,25-dihydroxyvitamin D3 [1,25(OH)2D3], regulates calcium metabolism, cellular proliferation and differentiation, immune responses, and other physiological processes. Recently, secondary bile acids such as lithocholic acid (LCA) were identified as endogenous VDR agonists. To identify structural determinants required for VDR activation by 1,25(OH)2D3 and LCA, we generated VDR mutants predicted to modulate ligand response based on sequence homology to pregnane X receptor, another bile acid-responsive nuclear receptor. In both vitamin D response element activation and mammalian two-hybrid assays, we found that VDR-S278V is activated by 1,25(OH)2D3 but not by LCA, whereas VDR-S237M can respond to LCA but not to 1,25(OH)2D3. Competitive ligand binding analysis reveals that LCA, but not 1,25(OH)2D3, effectively binds to VDR-S237M and both 1,25(OH)2D3 and LCA bind to VDR-S278V. We propose a docking model for LCA binding to VDR that is supported by mutagenesis data. Comparative analysis of the VDR-LCA and VDR-1,25(OH)2D3 structure-activity relationships should be useful in the development of bile acid-derived synthetic VDR ligands that selectively target VDR function in cancer and immune disorders without inducing adverse hypercalcemic effects.
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