4is8: Difference between revisions

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{{STRUCTURE_4is8|  PDB=4is8  |  SCENE=  }}
==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]] 2.78&Aring;' scene=''>
{{ABSTRACT_PUBMED_23737522}}
== Structural highlights ==
<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>
</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>
<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>
</table>
<div style="background-color:#fffaf0;">
== 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.


==Function==
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>
[[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.  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[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].
</div>
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:023737522</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Musille, P M.]]
[[Category: Musille, P M]]
[[Category: Ortlund, E A.]]
[[Category: Ortlund, E A]]
[[Category: Pathak, M C.]]
[[Category: Pathak, M C]]
[[Category: Ligand binding domain]]
[[Category: Ligand binding domain]]
[[Category: Transcription]]
[[Category: Transcription]]
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