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PDBsum entry 3cs4
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Gene regulation
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PDB id
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3cs4
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References listed in PDB file
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Key reference
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Title
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Structure-Based design of a superagonist ligand for the vitamin d nuclear receptor.
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Authors
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S.Hourai,
L.C.Rodrigues,
P.Antony,
B.Reina-San-Martin,
F.Ciesielski,
B.C.Magnier,
K.Schoonjans,
A.Mouriño,
N.Rochel,
D.Moras.
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Ref.
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Chem Biol, 2008,
15,
383-392.
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PubMed id
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Abstract
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Vitamin D nuclear receptor (VDR), a ligand-dependent transcriptional regulator,
is an important target for multiple clinical applications, such as osteoporosis
and cancer. Since exacerbated increase of calcium serum level is currently
associated with VDR ligands action, superagonists with low calcium serum levels
have been developed. Based on the crystal structures of human VDR (hVDR) bound
to 1alpha,25-dihydroxyvitamin D(3) and superagonists-notably, KH1060-we designed
a superagonist ligand. In order to optimize the aliphatic side chain
conformation with a subsequent entropy benefit, we incorporated an oxolane ring
and generated two stereo diasteromers, AMCR277A and AMCR277B. Only AMCR277A
exhibits superagonist activity in vitro, but is as calcemic in vivo as the
natural ligand. The crystal structures of the complexes between the ligand
binding domain of hVDR and these ligands provide a rational approach to the
design of more potent superagonist ligands for potential clinical application.
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