scholarly journals The effect of antagonists on the conformational exchange of the retinoid X receptor alpha ligand-binding domain

2009 ◽  
Vol 47 (12) ◽  
pp. 1071-1080 ◽  
Author(s):  
Jianyun Lu ◽  
Marcia I. Dawson ◽  
Qiong Ying Hu ◽  
Zebin Xia ◽  
Jesse D. Dambacher ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Retinoid X Receptor ◽  
Conformational Exchange ◽  
Receptor Alpha ◽  
Retinoid X Receptor Alpha

scholarly journals Characterization of the ligand binding domain of human retinoid X receptor alpha expressed in Escherichia coli

1994 ◽  
Vol 269 (28) ◽  
pp. 18662-18667
Author(s):  
L. Cheng ◽  
A.W. Norris ◽  
B.F. Tate ◽  
M. Rosenberger ◽  
J.F. Grippo ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Retinoid X Receptor ◽  
Receptor Alpha ◽  
Retinoid X Receptor Alpha

scholarly journals Heterodimeric interaction between retinoid X receptor alpha and orphan nuclear receptor OR1 reveals dimerization-induced activation as a novel mechanism of nuclear receptor activation.

1997 ◽  
Vol 17 (7) ◽  
pp. 3977-3986 ◽  
Author(s):  
F F Wiebel ◽  
J A Gustafsson
Keyword(s):  
Ligand Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Transcriptional Activation ◽  
Receptor Activation ◽  
Binding Domain ◽  
Retinoid X Receptor ◽  
Transcriptional Responses ◽  
Receptor Alpha ◽  
Retinoid X Receptor Alpha

OR1 is a member of the steroid/thyroid hormone nuclear receptor superfamily which has been described to mediate transcriptional responses to retinoids and oxysterols. On a DR4 response element, an OR1 heterodimer with the nuclear receptor retinoid X receptor alpha (RXR alpha) has been described to convey transcriptional activation in both the absence and presence of the RXR ligand 9-cis retinoic acid, the mechanisms of which have remained unclear. Here, we dissect the effects of RXR alpha and OR1 ligand-binding domain interaction on transcriptional regulation and the role of the respective carboxy-terminal activation domains (AF-2s) in the absence and presence of the RXR ligand, employing chimeras of the nuclear receptors containing the heterologous GAL4 DNA-binding domain as well as natural receptors. The results show that the interaction of the RXR and OR1 ligand-binding domains unleashes a transcription activation potential that is mainly dependent on the AF-2 of OR1, indicating that interaction with RXR activates OR1. This defines dimerization-induced activation as a novel function of heterodimeric interaction and mechanism of receptor activation not previously described for nuclear receptors. Moreover, we present evidence that activation of OR1 occurs by a conformational change induced upon heterodimerization with RXR.

scholarly journals Hereditary 1,25-Dihydroxyvitamin D Resistant Rickets due to a Mutation Causing Multiple Defects in Vitamin D Receptor Function

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5106-5114 ◽  
Author(s):  
Peter J. Malloy ◽  
Rong Xu ◽  
Lihong Peng ◽  
Sara Peleg ◽  
Abdullah Al-Ashwal ◽  
...  
Keyword(s):  
Vitamin D ◽  
Ligand Binding ◽  
Vitamin D Receptor ◽  
Novel Mutation ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Retinoid X Receptor ◽  
Vdr Gene ◽  
Dihydroxyvitamin D3 ◽  
Resistant Rickets

Abstract Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by mutations in the vitamin D receptor (VDR). We studied a young Saudi Arabian girl who exhibited the typical clinical features of HVDRR, but without alopecia. Analysis of her VDR gene revealed a homozygous T to C mutation in exon 7 that changed isoleucine to threonine at amino acid 268 (I268T). From crystallographic studies of the VDR ligand-binding domain, I268 directly interacts with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and is involved in the hydrophobic stabilization of helix H12. We recreated the I268T mutation and analyzed its effects on VDR function. In ligand binding assays, the I268T mutant VDR exhibited an approximately 5- to 10-fold lower affinity for [3H]1,25(OH)2D3 compared with the wild-type (WT) VDR. The I268T mutant required approximately a 65-fold higher concentration of 1,25(OH)2D3 to be equipotent in gene transactivation. Both retinoid X receptor heterodimerization and coactivator binding were reduced in the I268T mutant. Analogs of 1,25(OH)2D3 have been proposed as potential therapeutics for patients with HVDRR. Interestingly, in protease sensitivity assays, treatment with the potent vitamin D analog, 20-epi-1,25(OH)2D3, stabilized I268T mutant proteolytic fragments better than 1,25(OH)2D3. Moreover, 20-epi-1,25(OH)2D3 restored transactivation of the I268T mutant to levels exhibited by WT VDR treated with 1,25(OH)2D3. In conclusion, we describe a novel mutation, I268T, in the VDR ligand-binding domain that alters ligand binding, retinoid X receptor heterodimerization, and coactivator binding. These combined defects in VDR function cause resistance to 1,25(OH)2D3 action and result in the syndrome of HVDRR.

scholarly journals Defining the Communication between Agonist and Coactivator Binding in the Retinoid X Receptor α Ligand Binding Domain

2013 ◽  
Vol 289 (2) ◽  
pp. 814-826 ◽  
Author(s):  
LeeAnn J. Boerma ◽  
Gang Xia ◽  
Cheng Qui ◽  
Bryan D. Cox ◽  
Michael J. Chalmers ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Retinoid X Receptor

scholarly journals Polyunsaturated Fatty Acids Including Docosahexaenoic and Arachidonic Acid Bind to the Retinoid X Receptor α Ligand-binding Domain

2004 ◽  
Vol 3 (7) ◽  
pp. 692-703 ◽  
Author(s):  
Johan Lengqvist ◽  
Alexander Mata de Urquiza ◽  
Ann-Charlotte Bergman ◽  
Timothy M. Willson ◽  
Jan Sjövall ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Polyunsaturated Fatty Acids ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Retinoid X Receptor
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