4is8

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==Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors==
==Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors==
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<StructureSection load='4is8' size='340' side='right' caption='[[4is8]], [[Resolution|resolution]] 2.78&Aring;' scene=''>
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<StructureSection load='4is8' size='340' side='right'caption='[[4is8]], [[Resolution|resolution]] 2.78&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4is8]] is a 2 chain structure with 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=4IS8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4IS8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4is8]] 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=4IS8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IS8 FirstGlance]. <br>
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</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">B1F, CPF, FTF, NR5A2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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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]] 2.78&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4is8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4is8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4is8 RCSB], [http://www.ebi.ac.uk/pdbsum/4is8 PDBsum]</span></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=4is8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4is8 OCA], [https://pdbe.org/4is8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4is8 RCSB], [https://www.ebi.ac.uk/pdbsum/4is8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4is8 ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[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.
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The NR5A subfamily family of nuclear receptors (NRs) are important regulators of pluripotency, lipid and glucose homeostasis, and steroidogenesis. Liver receptor homologue 1 (LRH-1; NR5A2) and steroidogenic factor 1 (SF-1; NR5A1), have therapeutic potential for the treatment of metabolic and neoplastic disease; however, a poor understanding of their ligand regulation has hampered the pursuit of these proteins as pharmaceutical targets. In this study, we dissect how sequence variation among LRH-1 orthologs affects phospholipid (PL) binding and regulation. Both human and mouse LRH-1 (mLRH-1) respond to newly discovered medium chain PL agonists to modulate lipid and glucose homeostasis. These PLs activate human LRH-1 (hLRH-1) by altering receptor dynamics in a newly identified alternate activation function region. Mouse and Drosophila orthologs contain divergent sequence in this region potentially altering PL-driven activation. Structural evidence suggests that these sequence differences in mouse LRH-1 (mLRH-1) and Drosophila FTZ-f1 (dmFTZ-f1), confer at least partial ligand independence, making them poor models for hLRH-1 studies; however, the mechanisms of ligand independence remain untested. We show using structural and biochemical methods that the recent evolutionary divergence of the mLRH-1 stabilizes the active conformation in the absence of ligand, yet does not abrogate PL-dependent activation. We also show by mass spectrometry and biochemical assays that FTZ-f1 is incapable of PL binding. This work provides a structural mechanism for the differential tuning of PL-sensitivity in NR5A orthologs and supports the use of mice as viable therapeutic models for LRH-1-dependent diseases.
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Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors.,Musille PM, Pathak M, Lauer JL, Griffin PR, Ortlund EA J Biol Chem. 2013 Jun 4. PMID:23737522<ref>PMID:23737522</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
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</div>
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*[[Liver receptor homolog-1|Liver receptor homolog-1]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Musille, P M]]
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[[Category: Large Structures]]
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[[Category: Ortlund, E A]]
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[[Category: Musille PM]]
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[[Category: Pathak, M C]]
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[[Category: Ortlund EA]]
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[[Category: Ligand binding domain]]
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[[Category: Pathak MC]]
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[[Category: Transcription]]
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Current revision

Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors

PDB ID 4is8

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