4is8

</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>

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== 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<ref>PMID:23737522</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

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== References ==

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