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| | ==RORgamma in complex with agonist BIO592 and Coactivator EBI96== | | ==RORgamma in complex with agonist BIO592 and Coactivator EBI96== |
| - | <StructureSection load='5iz0' size='340' side='right' caption='[[5iz0]], [[Resolution|resolution]] 2.63Å' scene=''> | + | <StructureSection load='5iz0' size='340' side='right'caption='[[5iz0]], [[Resolution|resolution]] 2.63Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5iz0]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IZ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IZ0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5iz0]] is a 8 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=5IZ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IZ0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6F1:N-(4-ETHYL-3-OXO-3,4-DIHYDRO-2H-1,4-BENZOXAZIN-7-YL)-3,4-DIMETHYL-N-(2,2,2-TRIFLUOROETHYL)BENZENE-1-SULFONAMIDE'>6F1</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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]] 2.635Å</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=5iz0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iz0 OCA], [http://pdbe.org/5iz0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5iz0 RCSB], [http://www.ebi.ac.uk/pdbsum/5iz0 PDBsum]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6F1:N-(4-ETHYL-3-OXO-3,4-DIHYDRO-2H-1,4-BENZOXAZIN-7-YL)-3,4-DIMETHYL-N-(2,2,2-TRIFLUOROETHYL)BENZENE-1-SULFONAMIDE'>6F1</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=5iz0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iz0 OCA], [https://pdbe.org/5iz0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5iz0 RCSB], [https://www.ebi.ac.uk/pdbsum/5iz0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5iz0 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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Marcotte, D J]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Af2 helix]] | + | [[Category: Large Structures]] |
| - | [[Category: Agonist]] | + | [[Category: Marcotte DJ]] |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Nuclear hormone receptor]]
| + | |
| - | [[Category: Rorgamma]]
| + | |
| 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
BACKGROUND: The nuclear hormone receptor RORgamma regulates transcriptional genes involved in the production of the pro-inflammatory interleukin IL-17 which has been linked to autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. This transcriptional activity of RORgamma is modulated through a protein-protein interaction involving the activation function 2 (AF2) helix on the ligand binding domain of RORgamma and a conserved LXXLL helix motif on coactivator proteins. Our goal was to develop a RORgamma specific inverse agonist that would help down regulate pro-inflammatory gene transcription by disrupting the protein protein interaction with coactivator proteins as a therapeutic agent. RESULTS: We identified a novel series of synthetic benzoxazinone ligands having an agonist (BIO592) and inverse agonist (BIO399) mode of action in a FRET based assay. We show that the AF2 helix of RORgamma is proteolytically sensitive when inverse agonist BIO399 binds. Using x-ray crystallography we show how small modifications on the benzoxazinone agonist BIO592 trigger inverse agonism of RORgamma. Using an in vivo reporter assay, we show that the inverse agonist BIO399 displayed specificity for RORgamma over ROR sub-family members alpha and beta. CONCLUSION: The synthetic benzoxazinone ligands identified in our FRET assay have an agonist (BIO592) or inverse agonist (BIO399) effect by stabilizing or destabilizing the agonist conformation of RORgamma. The proteolytic sensitivity of the AF2 helix of RORgamma demonstrates that it destabilizes upon BIO399 inverse agonist binding perturbing the coactivator protein binding site. Our structural investigation of the BIO592 agonist and BIO399 inverse agonist structures identified residue Met358 on RORgamma as the trigger for RORgamma specific inverse agonism.
Structural determinant for inducing RORgamma specific inverse agonism triggered by a synthetic benzoxazinone ligand.,Marcotte DJ, Liu Y, Little K, Jones JH, Powell NA, Wildes CP, Silvian LF, Chodaparambil JV BMC Struct Biol. 2016 Jun 1;16(1):7. doi: 10.1186/s12900-016-0059-3. PMID:27246200[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Marcotte DJ, Liu Y, Little K, Jones JH, Powell NA, Wildes CP, Silvian LF, Chodaparambil JV. Structural determinant for inducing RORgamma specific inverse agonism triggered by a synthetic benzoxazinone ligand. BMC Struct Biol. 2016 Jun 1;16(1):7. doi: 10.1186/s12900-016-0059-3. PMID:27246200 doi:http://dx.doi.org/10.1186/s12900-016-0059-3
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