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PDBsum entry 6dup
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Nuclear protein
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PDB id
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6dup
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PDB id:
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| Name: |
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Nuclear protein
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Title:
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Crystal structure of pxr in complex with compound 7
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Structure:
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Nuclear receptor subfamily 1 group i member 2. Chain: a, b. Synonym: orphan nuclear receptor par1,orphan nuclear receptor pxr, pregnane x receptor,steroid and xenobiotic receptor,sxr. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: nr1i2, pxr. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.30Å
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R-factor:
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0.226
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R-free:
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0.266
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Authors:
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X.Chen,Y.Zhang,L.R.Mclean
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Key ref:
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R.J.Vaz
et al.
(2018).
Amelioration of PXR-mediated CYP3A4 induction by mGluR2 modulators.
Bioorg Med Chem Lett,
28,
3194-3196.
PubMed id:
DOI:
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Date:
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21-Jun-18
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Release date:
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29-Aug-18
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PROCHECK
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Headers
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References
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O75469
(NR1I2_HUMAN) -
Nuclear receptor subfamily 1 group I member 2 from Homo sapiens
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Seq:
Struc:
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434 a.a.
282 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 3 residue positions (black
crosses)
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DOI no:
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Bioorg Med Chem Lett
28:3194-3196
(2018)
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PubMed id:
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Amelioration of PXR-mediated CYP3A4 induction by mGluR2 modulators.
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R.J.Vaz,
Y.Li,
V.Chellaraj,
S.Reiling,
T.Kuntzweiler,
D.Yang,
H.Shen,
J.D.Batchelor,
Y.Zhang,
X.Chen,
L.R.McLean,
R.Kosley.
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ABSTRACT
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This work describes the rational amelioration of Cytochrome P450 4/5 (CYP3A4/5)
induction through the Pregnane-X Receptor (PXR) pathway in a series of compounds
that modulate the metabotropic glutamate Receptor 2 (mGluR2) via an allosteric
mechanism. The compounds were initially shown to induce CYP3A4/5 via the
gold-standard induction assay measured in primary human hepatocytes. This was
followed up by testing the compounds in a PXR assay which correlated well with
the assay in primary cells. Further, one of the compounds was crystallized with
PXR (pdb code 6DUP). Analysis of this co-crystal structure, together with
previously published PXR co-crystal structures, lead to modification ideas. The
compounds synthesized based on these ideas were shown not to be CYP3A4/5
inducers. The mGluR2 activity of the resulting compounds was maintained.
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