View source for Sandbox vdr

== 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.  VDR contains a ligand binding domain (<scene name='56/562378/Vit_d_receptor_ligand/1'>LBD</scene>) and <scene name='56/562378/Dbd/2'>DNA-binding domain (DBD)</scene>.


{{STRUCTURE_1db1|  PDB=1db1  |  SCENE=  }} 
===CRYSTAL STRUCTURE OF THE NUCLEAR RECEPTOR FOR VITAMIN D COMPLEXED TO VITAMIN D===
{{ABSTRACT_PUBMED_10678179}}

==Disease==
[[http://www.uniprot.org/uniprot/VDR_HUMAN VDR_HUMAN]] Defects in VDR are the cause of rickets vitamin D-dependent type 2A (VDDR2A) [MIM:[http://omim.org/entry/277440 277440]]. A disorder of vitamin D metabolism resulting in severe rickets, hypocalcemia and secondary hyperparathyroidism. Most patients have total alopecia in addition to rickets.<ref>PMID:2849209</ref><ref>PMID:8381803</ref><ref>PMID:1652893</ref><ref>PMID:2177843</ref><ref>PMID:8106618</ref><ref>PMID:8392085</ref><ref>PMID:7828346</ref><ref>PMID:8675579</ref><ref>PMID:8961271</ref><ref>PMID:9005998</ref> 

==Function==
[[http://www.uniprot.org/uniprot/VDR_HUMAN VDR_HUMAN]] Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Recruited to promoters via its interaction with the WINAC complex subunit BAZ1B/WSTF, which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.<ref>PMID:16252006</ref><ref>PMID:10678179</ref><ref>PMID:15728261</ref><ref>PMID:16913708</ref> 

==Mutation==
Serine/ 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/Vit_d_receptor_3m7r_serine/5'>serine</scene> is mutated it is replaced by with <scene name='56/562378/Vit_d_receptor_3m7r_serine/8'>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.


<scene name='56/562378/Vit_d_receptor_3m7r_serine/5'>Serine</scene> is replaced with 
<scene name='56/562378/Vit_d_receptor_3m7r_serine/9'>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.

==Crystal structure of the human VDR ligand binding domain bound to the synthetic agonist compound 2alpha-methyl-AMCR277A(C23S)==
Research 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. 



==About this Structure==
[[1db1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DB1 OCA]. On right hand side is Structure of human vitamin D receptor ligand-binding domain complex with vitamin D (PDB entry [[1db1]]).

==See Also==
*[[Vitamin D receptor|Vitamin D receptor]]


== 3D Structures of  vitamin D receptor==

Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}

===Vitamin D receptor ligand-binding domain===

[[3m7r]] - hVDR LBD (mutant) – human<br />

[[1db1]] – hVDR LBD + vitamin D <br />
[[1s0z]], [[1s19]], [[3a78]], [[4g2i]] - hVDR LBD + vitamin D derivative<br />
[[3ogt]], [[2ham]], [[2har]],  [[2has]], [[2hb7]], [[2hb8]], [[3p8x]], [[3az1]], [[3az2]], [[3az3]], [[3tkc]] - hVDR LBD + vitamin D analog<br />
[[3auq]], [[3aur]], [[3kpz]] - hVDR LBD (mutant) + vitamin D analog<br />
[[3a2i]], [[3a2j]], [[3b0t]], [[3ax8]], [[3vhw]] - hVDR LBD (mutant) + vitamin D derivative<br />
[[3a3z]], [[3a40]] - hVDR LBD + agonist<br />
[[1ie8]], [[1ie9]], [[3cs4]], [[3cs6]], [[1txi]] – hVDR LBD + superagonist <br />
[[3w5q]], [[3w5r]], [[3w5t]] - hVDR LBD + lithocholic acid derivative <br />

''Vitamin D receptor LBD complex with peptide''

[[1rjk]], [[1rk3]], [[1rkg]], [[1rkh]], [[2o4j]], [[2o4r]] – rVDR LBD (mutant) + peroxisome proliferator-activated receptor peptide – rat<br />
[[2zl9]], [[2zla]], [[2zlc]] - rVDR LBD + coactivator peptide DRIP + vitamin D analog<br />
[[3vrt]], [[3vru]], [[3vrv]], [[3vrw]] - rVDR LBD (mutant) + coactivator peptide DRIP + vitamin D analog<br />
[[2zfx]], [[3a2h]], [[2zxm]], [[2zxn]] - rVDR LBD + coactivator peptide DRIP<br />
[[3aun]], [[2zmh]], [[2zmi]], [[2zmj]], [[3afr]], [[3vjs]], [[3vjt]] - rVDR LBD (mutsant) + coactivator peptide DRIP<br />
[[2hbh]] - zVDR LBD + steroid receptor coactivator 1 peptide – zebrafish<br />
[[2hc4]] - zVDR LBD + steroid receptor coactivator 1 peptide + vitamin D<br />
[[2hcd]] - zVDR LBD + steroid receptor coactivator 1 peptide 

===Vitamin D receptor DNA-binding domain===

[[1kb2]] – hVDR DBD + osteopontin response element DNA<br />
[[1kb4]] – hVDR DBD + DR3 response element DNA<br />
[[1ynw]] – hVDR DBD (mutant) + DR3 response element DNA<br />
[[1kb6]] – hVDR DBD + osteocalcin response element DNA<br />

</StructureSection>
[[Category:Topic Page]]


==Reference==
<ref group="xtra">PMID:010678179</ref><ref group="xtra">PMID:011344298</ref><references group="xtra"/><references/>
[[Category: Homo sapiens]]
[[Category: Klaholz, B.]]
[[Category: Mitschler, A.]]
[[Category: Moras, D.]]
[[Category: Rochel, N.]]
[[Category: Wurtz, J M.]]
[[Category: Complex]]
[[Category: Gene regulation]]