1exa

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(New page: 200px<br /> <applet load="1exa" size="450" color="white" frame="true" align="right" spinBox="true" caption="1exa, resolution 1.59&Aring;" /> '''ENANTIOMER DISCRIMI...)
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[[Image:1exa.gif|left|200px]]<br />
 
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<applet load="1exa" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1exa, resolution 1.59&Aring;" />
 
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'''ENANTIOMER DISCRIMINATION ILLUSTRATED BY CRYSTAL STRUCTURES OF THE HUMAN RETINOIC ACID RECEPTOR HRARGAMMA LIGAND BINDING DOMAIN: THE COMPLEX WITH THE ACTIVE R-ENANTIOMER BMS270394.'''<br />
 
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==Overview==
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==ENANTIOMER DISCRIMINATION ILLUSTRATED BY CRYSTAL STRUCTURES OF THE HUMAN RETINOIC ACID RECEPTOR HRARGAMMA LIGAND BINDING DOMAIN: THE COMPLEX WITH THE ACTIVE R-ENANTIOMER BMS270394.==
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The human retinoic acid receptor (hRAR) is a member of the nuclear, receptor superfamily that regulates the transcription of target genes in a, ligand-dependent manner. The three hRAR isotypes are targets for retinoids, that are used in the treatment of various diseases, including breast, cancer and skin diseases. Drug efficiency and safety depend on the, pharmacological activity of enantiomers, which can differ because of the, chiral environment generated by the target. We report the crystal, structures of the hRARgamma ligand-binding domain bound to two, enantiomers, the active BMS270394 and the inactive BMS270395, solved at, 1.6 A and 1.7 A resolution, respectively. The crystal structures reveal, that in both enantiomers, the hydroxyl moiety attached to the chiral, center forms a hydrogen bond to the Met-272 sulfur atom, thus imposing a, conformation of BMS270395 that differs significantly from that observed, for BMS270394 and other known retinoids. BMS270395 adopts an energetically, unfavorable conformation, accounting for its inactivity; in contrast, the, conformation of BMS270394 is close to an energy minimum. Our, high-resolution data allow rationalization of enantiomer discrimination by, the receptor and provide a model system for the pharmacological properties, of enantiomeric pairs.
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<StructureSection load='1exa' size='340' side='right'caption='[[1exa]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1exa]] is a 1 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=1EXA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EXA FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.59&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=394:R-3-FLUORO-4-[2-HYDROXY-2-(5,5,8,8-TETRAMETHYL-5,6,7,8,-TETRAHYDRO-NAPHTALEN-2-YL)-ACETYLAMINO]-BENZOIC+ACID'>394</scene>, <scene name='pdbligand=LMU:DODECYL-ALPHA-D-MALTOSIDE'>LMU</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1exa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1exa OCA], [https://pdbe.org/1exa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1exa RCSB], [https://www.ebi.ac.uk/pdbsum/1exa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1exa ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/RARG_HUMAN RARG_HUMAN] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, acts mainly as an activator of gene expression due to weak binding to corepressors. Required for limb bud development. In concert with RARA or RARB, required for skeletal growth, matrix homeostasis and growth plate function (By similarity).
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ex/1exa_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1exa ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The human retinoic acid receptor (hRAR) is a member of the nuclear receptor superfamily that regulates the transcription of target genes in a ligand-dependent manner. The three hRAR isotypes are targets for retinoids that are used in the treatment of various diseases, including breast cancer and skin diseases. Drug efficiency and safety depend on the pharmacological activity of enantiomers, which can differ because of the chiral environment generated by the target. We report the crystal structures of the hRARgamma ligand-binding domain bound to two enantiomers, the active BMS270394 and the inactive BMS270395, solved at 1.6 A and 1.7 A resolution, respectively. The crystal structures reveal that in both enantiomers, the hydroxyl moiety attached to the chiral center forms a hydrogen bond to the Met-272 sulfur atom, thus imposing a conformation of BMS270395 that differs significantly from that observed for BMS270394 and other known retinoids. BMS270395 adopts an energetically unfavorable conformation, accounting for its inactivity; in contrast, the conformation of BMS270394 is close to an energy minimum. Our high-resolution data allow rationalization of enantiomer discrimination by the receptor and provide a model system for the pharmacological properties of enantiomeric pairs.
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==About this Structure==
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Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARgamma.,Klaholz BP, Mitschler A, Belema M, Zusi C, Moras D Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6322-7. PMID:10841540<ref>PMID:10841540</ref>
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1EXA 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 394 and LMU as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EXA OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Enantiomer discrimination illustrated by high-resolution crystal structures of the human nuclear receptor hRARgamma., Klaholz BP, Mitschler A, Belema M, Zusi C, Moras D, Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6322-7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10841540 10841540]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 1exa" style="background-color:#fffaf0;"></div>
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[[Category: Single protein]]
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[[Category: Belema, M.]]
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[[Category: Klaholz, B.P.]]
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[[Category: Mitschler, A.]]
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[[Category: Moras, D.]]
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[[Category: SPINE, Structural.Proteomics.in.Europe.]]
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[[Category: Zusi, C.]]
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[[Category: 394]]
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[[Category: LMU]]
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[[Category: antiparallel alpha-helical sandwich fold]]
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[[Category: enantiomer discrimination]]
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[[Category: retinoid ligand complexes]]
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[[Category: spine]]
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[[Category: structural genomics]]
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[[Category: structural proteomics in europe]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:47:24 2007''
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==See Also==
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*[[Retinoic acid receptor 3D structures|Retinoic acid receptor 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Belema M]]
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[[Category: Klaholz BP]]
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[[Category: Mitschler A]]
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[[Category: Moras D]]
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[[Category: Zusi C]]

Current revision

ENANTIOMER DISCRIMINATION ILLUSTRATED BY CRYSTAL STRUCTURES OF THE HUMAN RETINOIC ACID RECEPTOR HRARGAMMA LIGAND BINDING DOMAIN: THE COMPLEX WITH THE ACTIVE R-ENANTIOMER BMS270394.

PDB ID 1exa

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