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PDBsum entry 5e7v
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Transcription
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PDB id
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5e7v
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PDB id:
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| Name: |
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Transcription
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Title:
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Potent vitamin d receptor agonist
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Structure:
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Vitamin d3 receptor a. Chain: a. Synonym: vdr-a,1,25-dihydroxyvitamin d3 receptor a,nuclear receptor subfamily 1 group i member 1-a. Engineered: yes. Nuclear receptor coactivator 1. Chain: b. Engineered: yes
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Source:
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Danio rerio. Zebrafish. Organism_taxid: 7955. Gene: vdra, nr1i1a, vdr. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Homo sapiens. Human.
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Resolution:
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2.40Å
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R-factor:
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0.187
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R-free:
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0.213
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Authors:
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R.Otero,S.Seoane,R.Sigueiro,A.Y.Belorusova,M.A.Maestro,R.Perez- Fernandez,N.Rochel,A.Mourino
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Key ref:
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R.Otero
et al.
(2016).
Carborane-based design of a potent vitamin D receptor agonist.
Chem Sci,
7,
1033-1037.
PubMed id:
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Date:
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13-Oct-15
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Release date:
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25-Nov-15
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PROCHECK
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Headers
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References
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Q9PTN2
(VDRA_DANRE) -
Vitamin D3 receptor A from Danio rerio
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Seq:
Struc:
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453 a.a.
239 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Chem Sci
7:1033-1037
(2016)
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PubMed id:
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Carborane-based design of a potent vitamin D receptor agonist.
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R.Otero,
S.Seoane,
R.Sigüeiro,
A.Y.Belorusova,
M.A.Maestro,
R.Pérez-Fernández,
N.Rochel,
A.Mouriño.
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ABSTRACT
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The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy.
It is expressed in many tumors and its ligand shows anticancer actions. To
combine these properties with the application of boron neutron capture therapy
(BNCT), we design and synthesize a potent VDR agonist based on the skeleton of
the hormone 1α,25-dihydroxyvitamin D3(1,25D) and
ano-carborane (dicarba-o-closo-1,2-dodecaborane) at the end of its
side chain. The present ligand is the first secosteroidal analog with the
carborane unit that efficiently binds to VDR and functions as an agonist with
1,25D-like potency in transcriptional assay on vitamin D target genes. Moreover
it exhibits similar antiproliferative and pro-differentiating activities but is
significantly less hypercalcemic than 1,25D. The crystal structure of its
complex with VDR ligand binding domain reveals its binding mechanism involving
boron-mediated dihydrogen bonds that mimic vitamin D hydroxyl interactions. In
addition to the therapeutic interest, this study establishes the basis for the
design of new unconventional vitamin D analogs containing carborane moieties for
specific molecular recognition, and drug research and development.
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