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| | ==Ligand complex of RORg LBD== | | ==Ligand complex of RORg LBD== |
| - | <StructureSection load='5g46' size='340' side='right' caption='[[5g46]], [[Resolution|resolution]] 1.76Å' scene=''> | + | <StructureSection load='5g46' size='340' side='right'caption='[[5g46]], [[Resolution|resolution]] 1.76Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5g46]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5G46 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5G46 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5g46]] 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=5G46 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5G46 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6VD:2-ETHYL-4(1H)-QUINOLINONE'>6VD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.76Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5g42|5g42]], [[5g43|5g43]], [[5g44|5g44]], [[5g45|5g45]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6VD:2-ETHYL-4(1H)-QUINOLINONE'>6VD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=5g46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g46 OCA], [http://pdbe.org/5g46 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5g46 RCSB], [http://www.ebi.ac.uk/pdbsum/5g46 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5g46 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=5g46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g46 OCA], [https://pdbe.org/5g46 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5g46 RCSB], [https://www.ebi.ac.uk/pdbsum/5g46 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5g46 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: Guo, H]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hillertz, P]] | + | [[Category: Large Structures]] |
| - | [[Category: Xue, Y]] | + | [[Category: Guo H]] |
| - | [[Category: Dna binding protein]] | + | [[Category: Hillertz P]] |
| - | [[Category: Fragment screen]] | + | [[Category: Xue Y]] |
| - | [[Category: Rorg ligand]]
| + | |
| - | [[Category: Simultaneous binding]]
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| - | [[Category: Structure-based design]]
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| 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 receptor gamma t (RORgammat), as a master regulator of Th17 cell pathology, has become an attractive target for small-molecule drug discovery for the treatment of Th17-cell-related autoimmune diseases. A crystallographic fragment screening was carried out for RORgammat using the ligand binding domain. An overall hit rate of 5.5 % was obtained by screening 384 compounds in 96 cocktails. Five distinct hotspots were identified, and four regions of anchoring polar interactions were observed. In addition, significant induced fit was found for the binding of several fragments. Strikingly, a simultaneous binding of three fragments was revealed which presents interesting features including pi-pi stacking, multiple hydrogen bonds to the protein, and significant induced fit. Overall, the results offer a complete mapping of the ligand binding pocket and provide valuable inspiration in structure-based design for RORgammat lead generation and optimization. The crystallographic screening also resulted in fragment hits that bind at the surface away from the ligand binding pocket. This surface site is near the plausible dimer interface by analogy with other nuclear receptor systems, which can provide initial hints to explore alternative ways to modulate RORgammat through protein-protein interactions.
Fragment Screening of RORgammat Using Cocktail Crystallography: Identification of Simultaneous Binding of Multiple Fragments.,Xue Y, Guo H, Hillertz P ChemMedChem. 2016 Jul 19. doi: 10.1002/cmdc.201600242. PMID:27432277[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Xue Y, Guo H, Hillertz P. Fragment Screening of RORgammat Using Cocktail Crystallography: Identification of Simultaneous Binding of Multiple Fragments. ChemMedChem. 2016 Jul 19. doi: 10.1002/cmdc.201600242. PMID:27432277 doi:http://dx.doi.org/10.1002/cmdc.201600242
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