2ovh: Difference between revisions

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-[[Image:2ovh.gif|left|200px]]<br /><applet load="2ovh" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="2ovh, resolution 2.000&Aring;" />
-'''Progesterone Receptor with Bound Asoprisnil and a Peptide from the Co-Repressor SMRT'''<br />
-==Overview==
+==Progesterone Receptor with Bound Asoprisnil and a Peptide from the Co-Repressor SMRT==
-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.
+<StructureSection load='2ovh' size='340' side='right'caption='[[2ovh]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2ovh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OVH FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AS0:4-[(11BETA,17BETA)-17-METHOXY-17-(METHOXYMETHYL)-3-OXOESTRA-4,9-DIEN-11-YL]BENZALDEHYDE+OXIME'>AS0</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ovh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ovh OCA], [https://pdbe.org/2ovh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ovh RCSB], [https://www.ebi.ac.uk/pdbsum/2ovh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ovh ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/PRGR_HUMAN PRGR_HUMAN] The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor isoform B (PRB) is involved activation of c-SRC/MAPK signaling on hormone stimulation.<ref>PMID:15572662</ref> <ref>PMID:15798179</ref> <ref>PMID:17020914</ref> <ref>PMID:17347654</ref> <ref>PMID:17717077</ref> <ref>PMID:17173941</ref> <ref>PMID:18202149</ref>   Isoform A is inactive in stimulating c-Src/MAPK signaling on hormone stimulation.<ref>PMID:15572662</ref> <ref>PMID:15798179</ref> <ref>PMID:17020914</ref> <ref>PMID:17347654</ref> <ref>PMID:17717077</ref> <ref>PMID:17173941</ref> <ref>PMID:18202149</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ov/2ovh_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ovh ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-OVH 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].
+*[[Progesterone receptor|Progesterone receptor]]
+== References ==
-==Reference==
+<references/>
-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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17356170 17356170]
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Deng, S.J.]]
+[[Category: Deng S-J]]
-[[Category: Madauss, K.P.]]
+[[Category: Madauss KP]]
-[[Category: Short, S.A.]]
+[[Category: Short SA]]
-[[Category: Stewart, E.L.]]
+[[Category: Stewart EL]]
-[[Category: Williams, S.P.]]
+[[Category: Williams SP]]
-[[Category: AS0]]
-[[Category: asoprisnil]]
-[[Category: co-repressor]]
-[[Category: nuclear receptor]]
-[[Category: pr]]
-[[Category: progesterone receptor]]
-[[Category: steroid receptor]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:19:39 2008''