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Crystal Structures of the Vitamin D Nuclear Receptor Liganded with the Vitamin D Side Chain Analogues Calcipotriol and Seocalcitol, Receptor Agonists of Clinical Importance. Insights into a Structural Basis for the Switching of Calcipotriol to a Receptor Antagonist by Further Side Chain Modification

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Département de Biologie et de Génomique Structurales, IGBMC, CNRS/INSERM/Université Louis Pasteur, Parc d'Innovation BP10142, 67404 Illkirch Cedex, France
Cite this: J. Med. Chem. 2004, 47, 8, 1956–1961
Publication Date (Web):March 13, 2004
https://doi.org/10.1021/jm0310582
Copyright © 2004 American Chemical Society

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    Abstract

    Abstract Image

    The plethora of actions of 1α,25(OH)2D3 in various systems suggested wide clinical applications of vitamin D nuclear receptor (VDR) ligands in treatments of inflammation, dermatological indication, osteoporosis, cancers, and autoimmune diseases. More than 3000 vitamin D analogues have been synthesized in order to reduce the calcemic side effects while maintaining the transactivation potency of these ligands. Here, we report the crystal structures of VDR ligand binding domain bound to two vitamin D agonists of therapeutical interest, calcipotriol and seocalcitol, which are characterized by their side chain modifications. These structures show the conservation of the VDR structure and the adaptation of the side chain anchored by hydroxyl moieties. The structure of VDR-calcipotriol helps us to understand the structural basis for for the switching of calcipotriol to a receptor antagonist by further side chain modification. The VDR-seocalcitol structure, in comparison with the structure of VDR-KH1060, a superagonist ligand closely related to seocalcitol, shows adaptation of the D ring and position of C-21 in order to adapt its more rigid side chain.

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    §

     These authors contributed equally to this work.

     Present address:  Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, I-27100 Pavia, Italy, and Istituto di Biologia Cellulare, Consiglio Nazionale delle Ricerche, Campus A, Buzzati-Traverso, Via Ramarini, 32, 00016 Monterotondo Scalo, Rome, Italy.

    *

     To whom correspondence should be addressed. Phone:  (33) 3 88 65 33 51. Fax:  (33) 3 88 65 32 76. E-mail:  [email protected].

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