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| | <StructureSection load='6vif' size='340' side='right'caption='[[6vif]], [[Resolution|resolution]] 2.26Å' scene=''> | | <StructureSection load='6vif' size='340' side='right'caption='[[6vif]], [[Resolution|resolution]] 2.26Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6vif]] 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=6VIF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VIF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6vif]] 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=6VIF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VIF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QY4:N-[(8beta,11alpha,12alpha)-8-{[methyl(phenyl)amino]methyl}-1,6 7,14-dicycloprosta-1(6),2,4,7(14)-tetraen-11-yl]sulfuric+diamide'>QY4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.26Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR5A2, B1F, CPF, FTF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QY4:N-[(8beta,11alpha,12alpha)-8-{[methyl(phenyl)amino]methyl}-1,6 7,14-dicycloprosta-1(6),2,4,7(14)-tetraen-11-yl]sulfuric+diamide'>QY4</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6vif FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vif OCA], [http://pdbe.org/6vif PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vif RCSB], [http://www.ebi.ac.uk/pdbsum/6vif PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vif ProSAT]</span></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=6vif FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vif OCA], [https://pdbe.org/6vif PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vif RCSB], [https://www.ebi.ac.uk/pdbsum/6vif PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vif ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. | |
| | == 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. [[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.<ref>PMID:9430642</ref> | + | [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 6vif" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6vif" 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: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Cato, M L]] | + | [[Category: Cato ML]] |
| - | [[Category: Ortlund, E A]] | + | [[Category: Ortlund EA]] |
| - | [[Category: Agonist]]
| + | |
| - | [[Category: Ligand-binding domain]]
| + | |
| - | [[Category: Liver receptor homolog-1]]
| + | |
| - | [[Category: Nuclear protein]]
| + | |
| - | [[Category: Nuclear receptor]]
| + | |
| - | [[Category: Small molecule]]
| + | |
| 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
LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. We have developed a new synthetic approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand binding pocket to alter LRH-1 target gene expression.
Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition.,Cornelison JL, Cato ML, Johnson AM, D'Agostino EH, Melchers D, Patel AB, Mays SG, Houtman R, Ortlund EA, Jui NT Bioorg Med Chem Lett. 2020 Aug 15;30(16):127293. doi: 10.1016/j.bmcl.2020.127293., Epub 2020 May 30. PMID:32631515[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cornelison JL, Cato ML, Johnson AM, D'Agostino EH, Melchers D, Patel AB, Mays SG, Houtman R, Ortlund EA, Jui NT. Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition. Bioorg Med Chem Lett. 2020 Aug 15;30(16):127293. doi: 10.1016/j.bmcl.2020.127293., Epub 2020 May 30. PMID:32631515 doi:http://dx.doi.org/10.1016/j.bmcl.2020.127293
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