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| | ==Crystal structure of the orphan nuclear receptor ROR(gamma)t ligand-binding domain in complex with digoxin== | | ==Crystal structure of the orphan nuclear receptor ROR(gamma)t ligand-binding domain in complex with digoxin== |
| - | <StructureSection load='3b0w' size='340' side='right' caption='[[3b0w]], [[Resolution|resolution]] 2.20Å' scene=''> | + | <StructureSection load='3b0w' size='340' side='right'caption='[[3b0w]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3b0w]] 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=3B0W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3B0W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3b0w]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3B0W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3B0W FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DGX:DIGOXIN'>DGX</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DGX:DIGOXIN'>DGX</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RORC, NR1F3, RORG, RZRG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RORC, NR1F3, RORG, RZRG ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3b0w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3b0w OCA], [http://pdbe.org/3b0w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3b0w RCSB], [http://www.ebi.ac.uk/pdbsum/3b0w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3b0w 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=3b0w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3b0w OCA], [https://pdbe.org/3b0w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3b0w RCSB], [https://www.ebi.ac.uk/pdbsum/3b0w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3b0w ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN]] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. | + | [[https://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN]] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Ando, O]] | | [[Category: Ando, O]] |
| | [[Category: Fujita-Sato, S]] | | [[Category: Fujita-Sato, S]] |
| Structural highlights
Function
[RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.
Publication Abstract from PubMed
The retinoic acid-related orphan nuclear receptor gammat (RORgammat)/RORgamma2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORgammat and suppressed Th17 differentiation without affecting Th1 differentiation. To better understand the structural basis for the inhibitory activity of digoxin, we determined the crystal structure of the RORgammat ligand-binding domain in complex with digoxin at 2.2 A resolution. The structure reveals that digoxin binds to the ligand-binding pocket protruding between helices H3 and H11 from the pocket. In addition, digoxin disrupts the key interaction important for the agonistic activity, resulting in preventing the positioning of helix H12 in the active conformation, thus antagonizing coactivator interaction. Functional studies demonstrated that digoxin inhibited RORgammat activity and decreased IL-17 production but not RORalpha activity. Digoxin inhibited IL-17 production in CD4(+) T cells from experimental autoimmune encephalomyelitis mice. Our data indicates that RORgammat is a promising therapeutic target for Th17-derived autoimmune diseases and our structural data will help to design novel RORgammat antagonists.
Structural Basis of Digoxin That Antagonizes ROR{gamma}t Receptor Activity and Suppresses Th17 Cell Differentiation and Interleukin (IL)-17 Production.,Fujita-Sato S, Ito S, Isobe T, Ohyama T, Wakabayashi K, Morishita K, Ando O, Isono F J Biol Chem. 2011 Sep 9;286(36):31409-17. Epub 2011 Jul 6. PMID:21733845[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Fujita-Sato S, Ito S, Isobe T, Ohyama T, Wakabayashi K, Morishita K, Ando O, Isono F. Structural Basis of Digoxin That Antagonizes ROR{gamma}t Receptor Activity and Suppresses Th17 Cell Differentiation and Interleukin (IL)-17 Production. J Biol Chem. 2011 Sep 9;286(36):31409-17. Epub 2011 Jul 6. PMID:21733845 doi:10.1074/jbc.M111.254003
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