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[[Image:1fcz.gif|left|200px]]
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{{STRUCTURE_1fcz|  PDB=1fcz  |  SCENE=  }}
'''ISOTYPE SELECTIVITY OF THE HUMAN RETINOIC ACID NUCLEAR RECEPTOR HRAR: THE COMPLEX WITH THE PANAGONIST RETINOID BMS181156'''


==ISOTYPE SELECTIVITY OF THE HUMAN RETINOIC ACID NUCLEAR RECEPTOR HRAR: THE COMPLEX WITH THE PANAGONIST RETINOID BMS181156==
<StructureSection load='1fcz' size='340' side='right'caption='[[1fcz]], [[Resolution|resolution]] 1.38&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1fcz]] 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=1FCZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FCZ 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]] 1.38&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=156:4-[3-OXO-3-(5,5,8,8-TETRAMETHYL-5,6,7,8-TETRAHYDRO-NAPHTHALEN-2-YL)-PROPENYL]-BENZOIC+ACID'>156</scene>, <scene name='pdbligand=LMU:DODECYL-ALPHA-D-MALTOSIDE'>LMU</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=1fcz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fcz OCA], [https://pdbe.org/1fcz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1fcz RCSB], [https://www.ebi.ac.uk/pdbsum/1fcz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1fcz ProSAT]</span></td></tr>
</table>
== Function ==
[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).
== 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/fc/1fcz_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=1fcz ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The human retinoic acid receptor (hRAR) belongs to the family of nuclear receptors that regulate transcription in a ligand-dependent way. The isotypes RARalpha,beta and gamma are distinct pharmacological targets for retinoids that are involved in the treatment of various skin diseases and cancers, in particular breast cancer and acute promyelocytic leukemia. Therefore, synthetic retinoids have been developed aiming at isotype selectivity and reduced side-effects. We report the crystal structures of three complexes of the hRARgamma ligand-binding domain (LBD) bound to agonist retinoids that possess selectivity either for RARgamma (BMS184394) or for RARbeta/gamma (CD564), or that are potent for all RAR-isotypes (panagonist BMS181156). The high resolution data (1.3-1. 5 A) provide a description at the atomic level of the ligand pocket revealing the molecular determinants for the different degrees of ligand selectivity. The comparison of the complexes of the chemically closely related retinoids BMS184394 and CD564 shows that the side-chain of Met272 adopts different conformations depending on the presence of a hydrogen bond between its sulfur atom and the ligand. This accounts for their different isotype selectivity. On the other hand, the difference between the pan- and the RARbeta, gamma-selective agonist is probably due to a steric discrimination at the level of the 2-naphthoic acid moiety of CD564. Based on this study, we propose a model for a complex with the RARgamma-specific agonist CD666 that shows the possible applications for structure-based drug design of RAR isotype-selective retinoids.


==Overview==
Structural basis for isotype selectivity of the human retinoic acid nuclear receptor.,Klaholz BP, Mitschler A, Moras D J Mol Biol. 2000 Sep 8;302(1):155-70. PMID:10964567<ref>PMID:10964567</ref>
The human retinoic acid receptor (hRAR) belongs to the family of nuclear receptors that regulate transcription in a ligand-dependent way. The isotypes RARalpha,beta and gamma are distinct pharmacological targets for retinoids that are involved in the treatment of various skin diseases and cancers, in particular breast cancer and acute promyelocytic leukemia. Therefore, synthetic retinoids have been developed aiming at isotype selectivity and reduced side-effects. We report the crystal structures of three complexes of the hRARgamma ligand-binding domain (LBD) bound to agonist retinoids that possess selectivity either for RARgamma (BMS184394) or for RARbeta/gamma (CD564), or that are potent for all RAR-isotypes (panagonist BMS181156). The high resolution data (1.3-1. 5 A) provide a description at the atomic level of the ligand pocket revealing the molecular determinants for the different degrees of ligand selectivity. The comparison of the complexes of the chemically closely related retinoids BMS184394 and CD564 shows that the side-chain of Met272 adopts different conformations depending on the presence of a hydrogen bond between its sulfur atom and the ligand. This accounts for their different isotype selectivity. On the other hand, the difference between the pan- and the RARbeta, gamma-selective agonist is probably due to a steric discrimination at the level of the 2-naphthoic acid moiety of CD564. Based on this study, we propose a model for a complex with the RARgamma-specific agonist CD666 that shows the possible applications for structure-based drug design of RAR isotype-selective retinoids.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
1FCZ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FCZ OCA].
</div>
<div class="pdbe-citations 1fcz" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Structural basis for isotype selectivity of the human retinoic acid nuclear receptor., Klaholz BP, Mitschler A, Moras D, J Mol Biol. 2000 Sep 8;302(1):155-70. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10964567 10964567]
*[[Retinoic acid receptor 3D structures|Retinoic acid receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Klaholz, B P.]]
[[Category: Klaholz BP]]
[[Category: Mitschler, A.]]
[[Category: Mitschler A]]
[[Category: Moras, D.]]
[[Category: Moras D]]
[[Category: SPINE, Structural Proteomics in Europe.]]
[[Category: Antiparallel alpha-helical sandwich fold]]
[[Category: Drug design]]
[[Category: Isotype selectivity]]
[[Category: Retinoid ligand complex]]
[[Category: Spine]]
[[Category: Structural genomic]]
[[Category: Structural proteomics in europe]]
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