Selective Recognition of Vitamin D Receptor Conformations Mediates Promoter Selectivity of Vitamin D Analogs

1999 ◽  
Vol 55 (6) ◽  
pp. 1077-1087 ◽  
Author(s):  
Marcus Quack ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Selective Recognition ◽  
Vitamin D Analogs

scholarly journals New Ligands and New Insights for Vitamin D Receptor from Charge Density

2014 ◽  
Vol 70 (a1) ◽  
pp. C966-C966
Author(s):  
Maura Malińska ◽  
Andrzej Kutner ◽  
Krzysztof Woźniak
Keyword(s):  
Vitamin D ◽  
Hydrogen Bonds ◽  
Charge Density ◽  
Interaction Energy ◽  
Vitamin D Receptor ◽  
Electrostatic Interaction ◽  
Interaction Energies ◽  
Average Strength ◽  
Vitamin D Analogs ◽  
Wide Range

Vitamin D protective effects result from its role as a nuclear transcription factor that regulates cell growth, differentiation, and a wide range of cellular mechanisms crucial to the development and progression of cancer.[1] Many academic investigators and pharmaceutical companies try to develop calcitriol analogs that exhibit equal or even increased anti-proliferative activity while exhibiting a reduced tendency to cause hypercalcemia. Analysis of 24 Vitamin D analogs bearing similar molecular structures with a complex of a Vitamin D Receptor (VDR) enabled the design of new agonists (TB1, TB2, TB3 and TB4). Undertaken approach was to minimize the electrostatic interaction energies available after the reconstruction of charge density with the aid of the pseudoatom databank (UBDB[2]). Comprehensive studies revealed 29 residues crucial for agonist binding. Trp286, which is specific to VDR among the representatives of the Nuclear Receptor Family, plays the crucial role of positioning the ligand forming dispersive interactions, mostly C-H...π, with an average strength of -4 kcal mol-1. The ligand binding pocket is primarily composed of hydrophobic residues, however there are 6 hydrogen bonds characteristic for all the ligands. They electrostatic interaction energies strongly contribute to the total interaction energy, with an average strength of -8, -19, -11 and -12 kcal mol-1 for hydrogen bonds to Ser237, Arg274, Ser278 and Tyr143. The aliphatic chain of the Vitamin D analogs adopt an extended conformation and the 25-hydroxyl group is hydrogen bonded to His305 and His397 with electrostatic interaction energies of -13 and -11 kcal mol-1. The geometries of complexes of the proposed ligand with VDR were obtained by the docking procedure implemented in Autodock4.3[3]. New agonsits form all mentioned before interactions with VDR. The final results of electrostatic interaction energy for TB1 and TB2 are -153 and -120 kcal mol-1, and this results are the smallest among all studied Vitamin D analogs.

Altered Vitamin D receptor–coactivator interactions reflect superagonism of Vitamin D analogs

2005 ◽  
Vol 97 (1-2) ◽  
pp. 65-68 ◽  
Author(s):  
Guy Eelen ◽  
Lieve Verlinden ◽  
Mark Van Camp ◽  
Frank Claessens ◽  
Pierre De Clercq ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Vitamin D Analogs

Crystal Structures of Rat Vitamin D Receptor Bound to Adamantyl Vitamin D Analogs: Structural Basis for Vitamin D Receptor Antagonism and Partial Agonism

2008 ◽  
Vol 51 (17) ◽  
pp. 5320-5329 ◽  
Author(s):  
Makoto Nakabayashi ◽  
Sachiko Yamada ◽  
Nobuko Yoshimoto ◽  
Takashi Tanaka ◽  
Miharu Igarashi ◽  
...  
Keyword(s):  
Vitamin D ◽  
Crystal Structures ◽  
Vitamin D Receptor ◽  
Structural Basis ◽  
Partial Agonism ◽  
Receptor Antagonism ◽  
Vitamin D Analogs

Development of Vitamin D Analogs Modulating the Pocket Structure of Vitamin D Receptor

2014 ◽  
Vol 14 (21) ◽  
pp. 2378-2387 ◽  
Author(s):  
Keiko Yamamoto ◽  
Yasuaki Anami ◽  
Toshimasa Itoh
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Vitamin D Analogs

scholarly journals Antiproliferative Activity of Non-Calcemic Vitamin D Analogs on Human Melanoma Lines in Relation to VDR and PDIA3 Receptors

2018 ◽  
Vol 19 (9) ◽  
pp. 2583 ◽  
Author(s):  
Tomasz Wasiewicz ◽  
Anna Piotrowska ◽  
Justyna Wierzbicka ◽  
Andrzej Slominski ◽  
Michal Zmijewski
Keyword(s):  
Vitamin D ◽  
Cell Lines ◽  
Vitamin D Receptor ◽  
Melanoma Cell ◽  
Human Melanoma ◽  
Side Chain ◽  
Short Side ◽  
Vitamin D Analogs ◽  
Splicing Variants ◽  
Melanoma Cell Lines

Vitamin D is a precursor for secosteroidal hormones, which demonstrate pleiotropic biological activities, including the regulation of growth and the differentiation of normal and malignant cells. Our previous studies have indicated that the inhibition of melanoma proliferation by a short side-chain, low calcemic analog of vitamin D—21(OH)pD is not fully dependent on the expression of vitamin D receptor (VDR). We have examined the effects of classic vitamin D metabolites, 1,25(OH)2D3 and 25(OH)D3, and two low calcemic vitamin D analogs, (21(OH)pD and calcipotriol), on proliferation, mRNA expression and vitamin D receptor (VDR) translocation in three human melanoma cell lines: WM98, A375 and SK-MEL-188b (subline b of SK-MEL-188, which lost responsiveness to 1,25(OH)2D3 and became VDR−/−CYP27B1−/−). All tested compounds efficiently inhibited the proliferation of WM98 and A375 melanoma cells except SK-MEL-188b, in which only the short side-chain vitamin D analog—21(OH)pD was effective. Overall, 21(OH)pD was the most potent compound in all three melanoma cell lines in the study. The lack of responsiveness of SK-MEL-188b to 1,25(OH)2D3, 25(OH)D3 and calcipotriol is explained by a lack of characteristic transcripts for the VDR, its splicing variants as well as for vitamin D-activating enzyme CYP27B1. On the other hand, the expression of VDR and its splicing variants and other vitamin D related genes (RXR, PDIA3, CYP3A4, CYP2R1, CYP27B1, CYP24A1 and CYP11A1) was detected in WM98 and A375 melanomas with the transcript levels being modulated by vitamin D analogs. The expression of VDR isoforms in WM98 cells was stimulated strongly by calcipotriol. The antiproliferative activities of 21(OH)pD appear not to require VDR translocation to the nucleus, which explains the high efficacy of this noncalcemic pregnacalciferol analog in SK-MEL-188b melanoma, that is, VDR−/−. Therefore, we propose that 21(OH)pD is a good candidate for melanoma therapy, although the mechanism of its action remains to be defined.

scholarly journals Selective Interaction of Vitamin D Receptor with Transcriptional Coactivators by a Vitamin D Analog

1999 ◽  
Vol 19 (2) ◽  
pp. 1049-1055 ◽  
Author(s):  
Ken-Ichi Takeyama ◽  
Yoshikazu Masuhiro ◽  
Hiroaki Fuse ◽  
Hideki Endoh ◽  
Akiko Murayama ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Target Gene ◽  
Biological Action ◽  
Gene Promoters ◽  
Vitamin D Analogs ◽  
Dihydroxyvitamin D ◽  
Vitamin D Analog ◽  
Selective Interaction ◽  
Selective Interactions

ABSTRACT The nuclear vitamin D receptor (VDR) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor. A family of cotranscriptional activators (SRC-1, TIF2, and AIB-1) interacts with and activates the transactivation function of nuclear receptors in a ligand-dependent way. We examined interaction of VDR with these coactivators that was induced by several vitamin D analogs, since they exert differential subsets of the biological action of vitamin D through unknown mechanisms. Unlike other vitamin D analogs tested, OCT (22-oxa-1α,25-dihydroxyvitamin D3) induced interaction of VDR with TIF2 but not with SRC-1 or AIB-1. Consistent with these interactions, only TIF2 was able to potentiate the transactivation function of VDR bound to OCT. Thus, the present findings suggest that the structure of VDR is altered in a vitamin D analog-specific way, resulting in selective interactions of VDR with coactivators. Such selective interaction of coactivators with VDR may specify the array of biological actions of a vitamin D analog like OCT, possibly through activating a particular set of target gene promoters.

scholarly journals Differential Effects of 20-Epi Vitamin D Analogs on the Vitamin D Receptor Homodimer

1999 ◽  
Vol 14 (4) ◽  
pp. 509-517 ◽  
Author(s):  
Nicholas J. Koszewski ◽  
Timothy A. Reinhardt ◽  
Ronald L. Horst
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Differential Effects ◽  
Vitamin D Analogs
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