1u3r: Difference between revisions

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-[[Image:1u3r.gif|left|200px]]<br /><applet load="1u3r" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="1u3r, resolution 2.21&Aring;" />
-'''Crystal Structure of Estrogen Receptor beta complexed with WAY-338'''<br />
-==Overview==
+==Crystal Structure of Estrogen Receptor beta complexed with WAY-338==
-New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are &gt;100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --&gt; ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being &gt;200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
+<StructureSection load='1u3r' size='340' side='right'caption='[[1u3r]], [[Resolution|resolution]] 2.21&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1u3r]] is a 4 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=1U3R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1U3R 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]] 2.21&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=338:2-(5-HYDROXY-NAPHTHALEN-1-YL)-1,3-BENZOOXAZOL-6-OL'>338</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=1u3r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u3r OCA], [https://pdbe.org/1u3r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1u3r RCSB], [https://www.ebi.ac.uk/pdbsum/1u3r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1u3r ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/ESR2_HUMAN ESR2_HUMAN] Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner. Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual.
+== 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/u3/1u3r_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=1u3r ConSurf].
+<div style="clear:both"></div>
-==About this Structure==
+==See Also==
-U3R 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=338:'>338</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U3R OCA].
+*[[Estrogen receptor 3D structures|Estrogen receptor 3D structures]]
+__TOC__
-==Reference==
+</StructureSection>
-Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands., Malamas MS, Manas ES, McDevitt RE, Gunawan I, Xu ZB, Collini MD, Miller CP, Dinh T, Henderson RA, Keith JC Jr, Harris HA, J Med Chem. 2004 Oct 7;47(21):5021-40. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15456246 15456246]
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Collini, M D.]]
+[[Category: Collini MD]]
-[[Category: Dinh, T.]]
+[[Category: Dinh T]]
-[[Category: Gunawan, I.]]
+[[Category: Gunawan I]]
-[[Category: Harris, H A.]]
+[[Category: Harris HA]]
-[[Category: Henderson, R A.]]
+[[Category: Henderson RA]]
-[[Category: Jr., J C.Keith.]]
+[[Category: Keith Jr JC]]
-[[Category: Malamas, M S.]]
+[[Category: Malamas MS]]
-[[Category: Manas, E S.]]
+[[Category: Manas ES]]
-[[Category: McDevitt, R E.]]
+[[Category: McDevitt RE]]
-[[Category: Miller, C P.]]
+[[Category: Miller CP]]
-[[Category: Xu, Z B.]]
+[[Category: Xu ZB]]
-[[Category: 338]]
-[[Category: agonist]]
-[[Category: er]]
-[[Category: er-beta]]
-[[Category: estrogen]]
-[[Category: estrogen receptor]]
-[[Category: estrogen receptor beta]]
-[[Category: nuclear receptor]]
-[[Category: transcription factor]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:20:21 2008''