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* Residue conservation analysis
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Enzyme class:
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Chain A:
E.C.?
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Mol Endocrinol
21:1066-1081
(2007)
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PubMed id:
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A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator.
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K.P.Madauss,
E.T.Grygielko,
S.J.Deng,
A.C.Sulpizio,
T.B.Stanley,
C.Wu,
S.A.Short,
S.K.Thompson,
E.L.Stewart,
N.J.Laping,
S.P.Williams,
J.D.Bray.
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ABSTRACT
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Selective progesterone receptor modulators (SPRMs) have been suggested as
therapeutic agents for treatment of gynecological disorders. One such SPRM,
asoprisnil, was recently in clinical trials for treatment of uterine fibroids
and endometriosis. We present the crystal structures of progesterone receptor
(PR) ligand binding domain complexed with asoprisnil and the corepressors
nuclear receptor corepressor (NCoR) and SMRT. This is the first report of
steroid nuclear receptor crystal structures with ligand and corepressors. These
structures show PR in a different conformation than PR complexed with
progesterone (P4). We profiled asoprisnil in PR-dependent assays to understand
further the PR-mediated mechanism of action. We confirmed previous findings that
asoprisnil demonstrated antagonism, but not agonism, in a PR-B transfection
assay and the T47D breast cancer cell alkaline phosphatase activity assay.
Asoprisnil, but not RU486, weakly recruited the coactivators SRC-1 and AIB1.
However, asoprisnil strongly recruited the corepressor NCoR in a manner similar
to RU486. Unlike RU486, NCoR binding to asoprisnil-bound PR could be displaced
with equal affinity by NCoR or TIF2 peptides. We further showed that it weakly
activated T47D cell gene expression of Sgk-1 and PPL and antagonized P4-induced
expression of both genes. In rat leiomyoma ELT3 cells, asoprisnil demonstrated
partial P4-like inhibition of cyclooxygenase (COX) enzymatic activity and COX-2
gene expression. In the rat uterotrophic assay, asoprisnil demonstrated no
P4-like ability to oppose estrogen. Our data suggest that asoprisnil
differentially recruits coactivators and corepressors compared to RU486 or P4,
and this specific cofactor interaction profile is apparently insufficient to
oppose estrogenic activity in rat uterus.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.S.Veleiro,
L.D.Alvarez,
S.L.Eduardo,
and
G.Burton
(2010).
Structure of the glucocorticoid receptor, a flexible protein that can adapt to different ligands.
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ChemMedChem,
5,
649-659.
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A.le Maire,
C.Teyssier,
C.Erb,
M.Grimaldi,
S.Alvarez,
A.R.de Lera,
P.Balaguer,
H.Gronemeyer,
C.A.Royer,
P.Germain,
and
W.Bourguet
(2010).
A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor.
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Nat Struct Mol Biol,
17,
801-807.
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PDB codes:
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C.A.Phelan,
R.T.Gampe,
M.H.Lambert,
D.J.Parks,
V.Montana,
J.Bynum,
T.M.Broderick,
X.Hu,
S.P.Williams,
R.T.Nolte,
and
M.A.Lazar
(2010).
Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction.
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Nat Struct Mol Biol,
17,
808-814.
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PDB code:
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N.Chegini
(2010).
Proinflammatory and profibrotic mediators: principal effectors of leiomyoma development as a fibrotic disorder.
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Semin Reprod Med,
28,
180-203.
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H.Abdel-Hafiz,
M.L.Dudevoir,
and
K.B.Horwitz
(2009).
Mechanisms underlying the control of progesterone receptor transcriptional activity by SUMOylation.
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J Biol Chem,
284,
9099-9108.
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H.C.Raaijmakers,
J.E.Versteegh,
and
J.C.Uitdehaag
(2009).
The X-ray structure of RU486 bound to the progesterone receptor in a destabilized agonistic conformation.
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J Biol Chem,
284,
19572-19579.
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PDB code:
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S.Ellmann,
H.Sticht,
F.Thiel,
M.W.Beckmann,
R.Strick,
and
P.L.Strissel
(2009).
Estrogen and progesterone receptors: from molecular structures to clinical targets.
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Cell Mol Life Sci,
66,
2405-2426.
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S.W.Guo
(2009).
Epigenetics of endometriosis.
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Mol Hum Reprod,
15,
587-607.
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A.Morikawa,
N.Ohara,
Q.Xu,
K.Nakabayashi,
D.A.DeManno,
K.Chwalisz,
S.Yoshida,
and
T.Maruo
(2008).
Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer.
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Hum Reprod,
23,
944-951.
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C.Möller,
J.Hoffmann,
T.A.Kirkland,
and
W.Schwede
(2008).
Investigational developments for the treatment of progesterone-dependent diseases.
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Expert Opin Investig Drugs,
17,
469-479.
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K.Levitsky,
P.Szymanski,
F.Jin,
J.A.Meurer-Ogden,
and
R.N.Harkins
(2008).
Development and Validation of an Improved Inducer-Regulator Protein Complex in the pBRES-Regulated Expression System.
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Hum Gene Ther,
19,
1273-1282.
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M.C.Hodgson,
H.C.Shen,
A.N.Hollenberg,
and
S.P.Balk
(2008).
Structural basis for nuclear receptor corepressor recruitment by antagonist-liganded androgen receptor.
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Mol Cancer Ther,
7,
3187-3194.
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S.Ouzounian,
P.Bouchard,
and
N.Chabbert-Buffet
(2008).
Effects of antiprogestins on the uterus.
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Womens Health (Lond Engl),
4,
269-280.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
