6or1
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==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. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OR1 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6or1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6or1 OCA], [http://pdbe.org/6or1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6or1 RCSB], [http://www.ebi.ac.uk/pdbsum/6or1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6or1 ProSAT]</span></td></tr> | ||
| + | </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 == | ||
| + | [[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> | ||
| + | <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, S | + | <div class="pdbe-citations 6or1" style="background-color:#fffaf0;"></div> |
| - | [[Category: Ortlund, E | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Mays, S G]] | ||
| + | [[Category: Ortlund, E A]] | ||
| + | [[Category: Agonist]] | ||
| + | [[Category: Coactivator]] | ||
| + | [[Category: Nuclear receptor]] | ||
| + | [[Category: Transcription]] | ||
Revision as of 15:32, 28 August 2019
Human LRH-1 bound to the agonist 2N and a fragment of the Tif2 coregulator
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