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| - | ==Crytal Structure Analysis of the ROR gamma(C455E)== | + | ==Crystal Structure Analysis of the ROR gamma(C455E)== |
| | <StructureSection load='6j1l' size='340' side='right'caption='[[6j1l]], [[Resolution|resolution]] 2.30Å' scene=''> | | <StructureSection load='6j1l' size='340' side='right'caption='[[6j1l]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6j1l]] is a 3 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=6J1L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6J1L FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6j1l]] is a 3 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=6J1L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6J1L FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B6L:2-[4-(ethylsulfonyl)phenyl]-N-[2-fluoro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)[1,1-biphenyl]-4-yl]acetamide'>B6L</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]] 2.3Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B6L:2-[4-(ethylsulfonyl)phenyl]-N-[2-fluoro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)[1,1-biphenyl]-4-yl]acetamide'>B6L</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=6j1l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6j1l OCA], [http://pdbe.org/6j1l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6j1l RCSB], [http://www.ebi.ac.uk/pdbsum/6j1l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6j1l 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=6j1l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6j1l OCA], [https://pdbe.org/6j1l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6j1l RCSB], [https://www.ebi.ac.uk/pdbsum/6j1l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6j1l 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: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Li, C C]] | + | [[Category: Li CC]] |
| - | [[Category: Wu, X S]] | + | [[Category: Wu XS]] |
| - | [[Category: Zhang, Y]] | + | [[Category: Zhang Y]] |
| - | [[Category: Dna binding protein]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Lbd]]
| + | |
| - | [[Category: Ror gamma]]
| + | |
| 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
We report the design, optimization, and biological evaluation of nuclear receptor RORgamma inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC50 value of 30 nM in a cell-based reporter gene assay with good selectivity against other nuclear receptor subtypes. The cocrystal structure of 27 in complex with the RORgamma ligand binding domain provided a solid structural basis for its antagonistic mechanism. 27 potently inhibited cell growth, colony formation, and the expression of AR, AR-V7, and PSA. 27 also exhibited good metabolic stability and a pharmacokinetic profile with oral bioavailability of 59% and a half-life of 7.3 h. Notably, 27 demonstrated promising therapeutic effects with significant tumor growth inhibition in a prostate cancer xenograft model in mice. The potent, selective, metabolically stable, and orally available RORgamma inverse agonists represent a new class of compounds as potential therapeutics against prostate cancer.
Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORgamma Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer.,Zhang Y, Wu X, Xue X, Li C, Wang J, Wang R, Zhang C, Wang C, Shi Y, Zou L, Li Q, Huang Z, Hao X, Loomes K, Wu D, Chen HW, Xu J, Xu Y J Med Chem. 2019 Apr 22. doi: 10.1021/acs.jmedchem.9b00327. PMID:30964293[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang Y, Wu X, Xue X, Li C, Wang J, Wang R, Zhang C, Wang C, Shi Y, Zou L, Li Q, Huang Z, Hao X, Loomes K, Wu D, Chen HW, Xu J, Xu Y. Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORgamma Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer. J Med Chem. 2019 Apr 22. doi: 10.1021/acs.jmedchem.9b00327. PMID:30964293 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00327
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