View source for 5lyq


==Crystal structure of the Retinoic Acid Receptor alpha in complex with a synthetic spiroketal agonist and a fragment of the TIF2 co-activator.==
<StructureSection load='5lyq' size='340' side='right'caption='[[5lyq]], [[Resolution|resolution]] 2.17&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5lyq]] 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=5LYQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LYQ 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]] 2.17&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7BE:(2~{R})-6,6,9,9-TETRAMETHYLSPIRO[3,4,7,8-TETRAHYDROBENZO[G]CHROMENE-2,2-3,4-DIHYDROCHROMENE]-6-CARBOXYLIC+ACID'>7BE</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=5lyq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lyq OCA], [https://pdbe.org/5lyq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lyq RCSB], [https://www.ebi.ac.uk/pdbsum/5lyq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lyq ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_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. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR 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, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure-based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co-activator recruitment. We solved the crystal structure of the spiroketal-hRXRalpha-TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co-crystal structure, the first of a designed spiroketal-protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.

Designed Spiroketal Protein Modulation.,Scheepstra M, Andrei SA, Unver MY, Hirsch AK, Leysen S, Ottmann C, Brunsveld L, Milroy LG Angew Chem Int Ed Engl. 2017 Apr 13. doi: 10.1002/anie.201612504. PMID:28407400<ref>PMID:28407400</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5lyq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Andrei SA]]
[[Category: Ottmann C]]