6or1: Difference between revisions
New page: '''Unreleased structure''' The entry 6or1 is ON HOLD Authors: Mays, S.G., Ortlund, E.A. Description: Human LRH-1 bound to the agonist 2N and a fragment of the Tif2 coregulator [[Catego... |
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==Human LRH-1 bound to the agonist 2N and a fragment of the Tif2 coregulator== | |||
<StructureSection load='6or1' size='340' side='right'caption='[[6or1]], [[Resolution|resolution]] 2.17Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6or1]] 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=6OR1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OR1 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]] 2.174Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N27:N-[(1S,3aR,6aR)-5-hexyl-4-phenyl-3a-(1-phenylethenyl)-1,2,3,3a,6,6a-hexahydropentalen-1-yl]acetamide'>N27</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=6or1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6or1 OCA], [https://pdbe.org/6or1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6or1 RCSB], [https://www.ebi.ac.uk/pdbsum/6or1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6or1 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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Mays | <div class="pdbe-citations 6or1" style="background-color:#fffaf0;"></div> | ||
[[Category: Ortlund | |||
==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]] | |||
Latest revision as of 10:15, 11 October 2023
Human LRH-1 bound to the agonist 2N and a fragment of the Tif2 coregulatorHuman LRH-1 bound to the agonist 2N and a fragment of the Tif2 coregulator
Structural highlights
FunctionNR5A2_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 PubMedAs 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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