Sandbox vdr: Difference between revisions
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== Vitamin D Receptor == | == Vitamin D Receptor == | ||
'''Vitamin D receptor''' (<scene name='56/562378/Vit_d_receptor_3m7r/3'>VDR</scene>) is a transcription factor. Upon binding to vitamin D, VDR forms a heterodimer with retinoid-X receptor and binds to hormone response receptors on DNA causing gene expression. The <scene name='56/562378/Vit_d_receptor_ligand/1'>vitamin D hormone</scene> (in green) binds to receptors in its target cells, controlling the synthesis of many different proteins involved in calcium transport and utilization. VDR contains two domains: a <scene name='56/562378/Lbd/1'>ligand binding domain (LBD)</scene> that binds to the hormone and <scene name='56/562378/Dbd/2'>DNA-binding domain (DBD)</scene> that binds to DNA. It pairs up with a similar protein, 9-cis retinoic acid receptor (RXR), and together they bind to the DNA, activating synthesis in some cases and repressing it in others. | {{STRUCTURE_1db1| PDB=1db1 | SCENE= }} | ||
'''Vitamin D receptor''' (<scene name='56/562378/Vit_d_receptor_3m7r/3'>VDR</scene>) is a transcription factor. Upon binding to vitamin D, VDR forms a heterodimer with retinoid-X receptor and binds to hormone response receptors on DNA causing gene expression. The <scene name='56/562378/Vit_d_receptor_ligand/1'>vitamin D hormone</scene> (in green) binds to receptors in its target cells, controlling the synthesis of many different proteins involved in calcium transport and utilization. VDR contains two domains: a <scene name='56/562378/Lbd/1'>ligand binding domain (LBD)</scene> that binds to the hormone (grey) and <scene name='56/562378/Dbd/2'>DNA-binding domain (DBD)</scene> that binds to DNA. (Green and blue are two same VDR structures). It pairs up with a similar protein, 9-cis retinoic acid receptor (RXR), and together they bind to the DNA, activating synthesis in some cases and repressing it in others. | |||
===Crystal Structure of the nuclear receptor for Vitamnin D complexed to Vitamin D=== | ===Crystal Structure of the nuclear receptor for Vitamnin D complexed to Vitamin D=== | ||
{{ABSTRACT_PUBMED_10678179}} | {{ABSTRACT_PUBMED_10678179}} | ||
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==Mutation== | ==Mutation== | ||
<StructureSection load='VDRmutation1.pdb' size=' | <StructureSection load='VDRmutation1.pdb' size='350' side='right' caption='Mutation of Vitamin D Receptor' scene=''>In the article, "Phosphorylation of the Human Vitamin D receptor by Protein Kinase C" by Hsieh, J. et al, they presented their research on the mutation of serine to glycine and aspartic acid. They mentioned that amino acids like serine and threonine kinase plays a crucial role in signal transduction pathways drawn out by variety of growth factors, hormones, and neurotransmitters. When <scene name='56/562378/Serine_final/1'>serine</scene> is mutated it is replaced with a <scene name='56/562378/Glycine_final/1'>glycine</scene> which results in an inhibition of transcriptional activation. When transcription is inhibited it results in p53 accumulation, which activates and promotes p53 translocation into mitochondria leading to apoptosis. Transcription inhibition is useful in cancer patients and so can be used as treatment option. These are the outcomes of the mutation, with the research still in the process to find the potential cure for tumors. | ||
<scene name='56/562378/ | <scene name='56/562378/Serine_final/1'>Serine</scene> is replaced with <scene name='56/562378/Asparticacid_final/1'>aspartic acid</scene> when mutated creating a negative charge. The negative charge at the residue inhibits DNA binding which cause a down – regulation of VDR activity. VDR needs DNA binding in order for it to be activated which is only possible with a serine residue. Research is still continuing to find a therapeutic cause for this mutation. | ||
<scene name='56/562378/ | |||
</StructureSection> | </StructureSection> | ||
==Crystal structure of the human VDR ligand binding domain bound to the synthetic agonist compound 2alpha-methyl-AMCR277A(C23S)== | ==Crystal structure of the human VDR ligand binding domain bound to the synthetic agonist compound 2alpha-methyl-AMCR277A(C23S)== | ||
<StructureSection load='3a3z' size='350' side='right' caption='Synthetic agonist (PDB entry [[3a3z]])' scene=''>The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. In the article, "Structure-function relationships and crystal structures of the vitamin D receptor bound 2 alpha-methyl-(20S,23S)- and 2 alpha-methyl-(20S,23R)-epoxymethano-1 alpha,25-dihydroxyvitamin D3" by Antony, P. et al, they showed that <scene name='56/562378/3a3z/1'>the synthetic analogue (20S,23S)-epoxymethano-1alpha,25-dihydroxyvitamin D(3) (2a)</scene> acts as a 1alpha,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1alpha,25(OH)(2)D(3), 2alpha-methyl-1alpha,25(OH)(2)D(3), or 2a, we designed a novel analogue, 2alpha-methyl-(20S,23S)-epoxymethano-1alpha,25-dihydroxyvitamin D(3) (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes. | |||
</StructureSection> | |||
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==See Also== | ==See Also== | ||
*[[ | *[[3a3z|3a3z]] | ||