View source for 6oqy


==Human LRH-1 bound to the agonist 6N and a fragment of the Tif2 coregulator==
<StructureSection load='6oqy' size='340' side='right'caption='[[6oqy]], [[Resolution|resolution]] 2.23&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6oqy]] 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=6OQY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OQY 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]] 2.23&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N2J:N-[(1S,3aR,6aR)-5-hexyl-4-phenyl-3a-(1-phenylethenyl)-1,2,3,3a,6,6a-hexahydropentalen-1-yl]sulfuric+diamide'>N2J</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=6oqy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oqy OCA], [https://pdbe.org/6oqy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oqy RCSB], [https://www.ebi.ac.uk/pdbsum/6oqy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oqy ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NR5A2_HUMAN NR5A2_HUMAN] Binds to the sequence element 5'-AACGACCGACCTTGAG-3' of the enhancer II of hepatitis B virus genes, a critical cis-element of their expression and regulation. May be responsible for the liver-specific activity of enhancer II, probably in combination with other hepatocyte transcription factors. Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver. May also contribute to the regulation of pancreas-specific genes and play important roles in embryonic development.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
As a key regulator of metabolism and inflammation, the orphan nuclear hormone receptor, Liver Receptor Homolog-1 (LRH-1), has potential as a therapeutic target for diabetes, nonalcoholic fatty liver disease, and inflammatory bowel diseases. Discovery of LRH-1 modulators has been difficult, in part due to the tendency for synthetic compounds to bind unpredictably within the lipophilic binding pocket. Using a structure-guided approach, we exploited a newly-discovered polar interaction to lock agonists in a consistent orientation. This enabled the discovery of the first low nanomolar LRH-1 agonist, one hundred times more potent than the best previous modulator. We elucidate a novel mechanism of action that relies upon specific polar interactions deep in the LRH-1 binding pocket. In an organoid model of inflammatory bowel disease, the new agonist increases expression of LRH-1-conrolled steroidogenic genes and promotes anti-inflammatory gene expression changes. These studies constitute major progress in developing LRH-1 modulators with potential clinical utility.

Development of the first low nanomolar Liver Receptor Homolog-1 agonist through structure-guided design.,Mays S, Flynn AR, Cornelison J, Okafor CD, Wang H, Wang G, Huang X, Donaldson H, Millings E, Polavarapu R, Moore D, Calvert J, Jui NT, Ortlund EA J Med Chem. 2019 Aug 16. doi: 10.1021/acs.jmedchem.9b00753. PMID:31419141<ref>PMID:31419141</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6oqy" style="background-color:#fffaf0;"></div>

==See Also==
*[[Liver receptor homolog-1|Liver receptor homolog-1]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mays SG]]
[[Category: Ortlund EA]]