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| | <StructureSection load='6tlm' size='340' side='right'caption='[[6tlm]], [[Resolution|resolution]] 2.32Å' scene=''> | | <StructureSection load='6tlm' size='340' side='right'caption='[[6tlm]], [[Resolution|resolution]] 2.32Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6tlm]] is a 1 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=6TLM OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TLM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6tlm]] is a 1 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=6TLM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TLM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MJE:4-[1-[2,6-bis(chloranyl)phenyl]carbonyl-5-methyl-thieno[3,2-c]pyrazol-3-yl]benzoic+acid'>MJE</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]] 2.321Å</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=MJE:4-[1-[2,6-bis(chloranyl)phenyl]carbonyl-5-methyl-thieno[3,2-c]pyrazol-3-yl]benzoic+acid'>MJE</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6tlm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tlm OCA], [http://pdbe.org/6tlm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tlm RCSB], [http://www.ebi.ac.uk/pdbsum/6tlm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tlm 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=6tlm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tlm OCA], [https://pdbe.org/6tlm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tlm RCSB], [https://www.ebi.ac.uk/pdbsum/6tlm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tlm 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: Brunsveld, L]] | + | [[Category: Brunsveld L]] |
| - | [[Category: Meijer, F A]] | + | [[Category: Meijer FA]] |
| - | [[Category: Vries, R M.J M.de]] | + | [[Category: De Vries RMJM]] |
| - | [[Category: Allosteric]]
| + | |
| - | [[Category: Gene regulation]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Inverse agonist]]
| + | |
| - | [[Category: Nuclear receptor]]
| + | |
| 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 demand for allosteric targeting of nuclear receptors is high, but examples are limited, and structural information is scarce. The retinoic acid-related orphan receptor gamma t (RORgammat) is an important transcriptional regulator for the differentiation of T helper 17 cells for which the first, and some of the most promising, examples of allosteric nuclear receptor modulation have been reported and structurally proven. In a 2015 patent, filed by the pharmaceutical company Glenmark, a new class of small molecules was reported that act as potent inverse agonists for RORgammat. A compound library around the central thienopyrazole scaffold captured a clear structure-activity relationship, but the binding mechanism of this new class of RORgammat modulators has not been elucidated. Using a combination of biochemical and X-ray crystallography studies, here the allosteric mechanism for the inverse agonism for the most potent compound, classified in the patent as "example 13", is reported, providing a strongly desired additional example of allosteric nuclear receptor targeting.
Elucidation of an allosteric mode-of-action for a thienopyrazole RORgammat inverse agonist.,de Vries RMJM, Meijer FA, Doveston RG, Brunsveld L ChemMedChem. 2020 Feb 13. doi: 10.1002/cmdc.202000044. PMID:32053744[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ de Vries RMJM, Meijer FA, Doveston RG, Brunsveld L. Elucidation of an allosteric mode-of-action for a thienopyrazole RORgammat inverse agonist. ChemMedChem. 2020 Feb 13. doi: 10.1002/cmdc.202000044. PMID:32053744 doi:http://dx.doi.org/10.1002/cmdc.202000044
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