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| | ==Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors== | | ==Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors== |
| - | <StructureSection load='4is8' size='340' side='right' caption='[[4is8]], [[Resolution|resolution]] 2.78Å' scene=''> | + | <StructureSection load='4is8' size='340' side='right'caption='[[4is8]], [[Resolution|resolution]] 2.78Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4is8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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> | + | <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> |
| - | </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 HUMAN])</td></tr> | + | </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=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> |
| - | <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://pdbe.org/4is8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4is8 RCSB], [http://www.ebi.ac.uk/pdbsum/4is8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4is8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4is8" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4is8" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Liver receptor homolog-1|Liver receptor homolog-1]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Musille, P M]] | + | [[Category: Large Structures]] |
| - | [[Category: Ortlund, E A]] | + | [[Category: Musille PM]] |
| - | [[Category: Pathak, M C]] | + | [[Category: Ortlund EA]] |
| - | [[Category: Ligand binding domain]] | + | [[Category: Pathak MC]] |
| - | [[Category: Transcription]]
| + | |
| Structural highlights
Function
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.
Publication Abstract from PubMed
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Musille PM, Pathak M, Lauer JL, Griffin PR, Ortlund EA. Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors. J Biol Chem. 2013 Jun 4. PMID:23737522 doi:10.1074/jbc.M113.472837
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