2ovh
From Proteopedia
(New page: 200px<br /> <applet load="2ovh" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ovh, resolution 2.000Å" /> '''Progesterone Recep...) |
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| - | [[Image:2ovh.gif|left|200px]]<br /> | + | [[Image:2ovh.gif|left|200px]]<br /><applet load="2ovh" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2ovh" size=" | + | |
caption="2ovh, resolution 2.000Å" /> | caption="2ovh, resolution 2.000Å" /> | ||
'''Progesterone Receptor with Bound Asoprisnil and a Peptide from the Co-Repressor SMRT'''<br /> | '''Progesterone Receptor with Bound Asoprisnil and a Peptide from the Co-Repressor SMRT'''<br /> | ||
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==Overview== | ==Overview== | ||
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 (P(4)). 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 P(4)-induced expression of both genes. In rat, leiomyoma ELT3 cells, asoprisnil demonstrated partial P(4)-like inhibition, of cyclooxygenase (COX) enzymatic activity and COX-2 gene expression. In, the rat uterotrophic assay, asoprisnil demonstrated no P(4)-like ability, to oppose estrogen. Our data suggest that asoprisnil differentially, recruits coactivators and corepressors compared to RU486 or P(4), and this, specific cofactor interaction profile is apparently insufficient to oppose, estrogenic activity in rat uterus. | 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 (P(4)). 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 P(4)-induced expression of both genes. In rat, leiomyoma ELT3 cells, asoprisnil demonstrated partial P(4)-like inhibition, of cyclooxygenase (COX) enzymatic activity and COX-2 gene expression. In, the rat uterotrophic assay, asoprisnil demonstrated no P(4)-like ability, to oppose estrogen. Our data suggest that asoprisnil differentially, recruits coactivators and corepressors compared to RU486 or P(4), and this, specific cofactor interaction profile is apparently insufficient to oppose, estrogenic activity in rat uterus. | ||
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| - | ==Disease== | ||
| - | Known disease associated with this structure: Progesterone resistance, 264080 (2) OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607311 607311]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2OVH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with AS0 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 2OVH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=AS0:'>AS0</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OVH OCA]. |
==Reference== | ==Reference== | ||
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[[Category: steroid receptor]] | [[Category: steroid receptor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:19:39 2008'' |
Revision as of 13:19, 23 January 2008
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Progesterone Receptor with Bound Asoprisnil and a Peptide from the Co-Repressor SMRT
Overview
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 (P(4)). 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 P(4)-induced expression of both genes. In rat, leiomyoma ELT3 cells, asoprisnil demonstrated partial P(4)-like inhibition, of cyclooxygenase (COX) enzymatic activity and COX-2 gene expression. In, the rat uterotrophic assay, asoprisnil demonstrated no P(4)-like ability, to oppose estrogen. Our data suggest that asoprisnil differentially, recruits coactivators and corepressors compared to RU486 or P(4), and this, specific cofactor interaction profile is apparently insufficient to oppose, estrogenic activity in rat uterus.
About this Structure
2OVH is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator., Madauss KP, Grygielko ET, Deng SJ, Sulpizio AC, Stanley TB, Wu C, Short SA, Thompson SK, Stewart EL, Laping NJ, Williams SP, Bray JD, Mol Endocrinol. 2007 May;21(5):1066-81. Epub 2007 Mar 13. PMID:17356170
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