1txi

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spinqualitylabelsall models 1txi, resolution 1.9Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of the vdr ligand binding domain complexed to TX522

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Two 14-epi-analogs of 1,25-dihydroxyvitamin D3 [1,25-(OH)(2)D(3)], 19-nor-14-epi-23-yne-1,25-(OH)2D3 (TX522) and, 19-nor-14,20-bisepi-23-yne-1,25-(OH)2D3 (TX527), show enhanced, antiproliferative (at least 10-fold) and markedly lower calcemic effects, both in vitro and in vivo, compared with 1,25-(OH)2D3. This study aimed to, evaluate their superagonistic effect at the level of interaction between, the Vitamin D receptor (VDR) and coactivators. Mammalian two-hybrid assays, with VP16-fused VDR and GAL4-DNA-binding-domain-fused steroid receptor, coactivator 1 (SRC-1), transcriptional intermediary factor 2 (Tif2), or, DRIP205 showed the 14-epi-analogs to be more potent inducers of, VDR-coactivator interactions than 1,25-(OH)2D3 (up to 16- and 20-fold, stronger induction of VDR-SRC-1 interaction for TX522 and TX527 at 10(-10), M). Similar assays in which metabolism of 1,25-(OH)2D3 was blocked with, VID400, a selective inhibitor of the 1,25-(OH)2D3-metabolizing enzyme, CYP24, showed that the enhanced potency of these analogs in establishing, VDR-coactivator interactions can only partially be accounted for by their, increased resistance to metabolic degradation. Crystallization of TX522, complexed to the ligand binding domain of the human VDR demonstrated that, the epi-configuration of C14 caused the CD ring of the ligand to shift by, 0.5 angstroms, thereby bringing the C12 atom into closer contact with, Val300. Moreover, C22 of TX522 made an additional contact with the CD1, atom of Ile268 because of the rigidity of the triple bond-containing side, chain. The position and conformation of the activation helix H12 of VDR, was strictly maintained. In conclusion, this study provides deeper insight, into the docking of TX522 in the LBP and shows that stronger, VDR-coactivator interactions underlie the superagonistic activity of the, two 14-epi-analogs.

Disease

Known diseases associated with this structure: Osteoporosis, involutional, 166710 (1) OMIM:[601769], Rickets, vitamin D-resistant, type IIA OMIM:[601769]

About this Structure

1TXI is a Single protein structure of sequence from Homo sapiens with TX5 as ligand. Full crystallographic information is available from OCA.

Reference

Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by vitamin D receptor-coactivator interaction., Eelen G, Verlinden L, Rochel N, Claessens F, De Clercq P, Vandewalle M, Tocchini-Valentini G, Moras D, Bouillon R, Verstuyf A, Mol Pharmacol. 2005 May;67(5):1566-73. Epub 2005 Feb 22. PMID:15728261

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