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6q6o

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RORCVAR2 (RORGT, 264-499) IN COMPLEX WITH COMPOUND 2 AT 2.3A: Identification of N-aryl imidazoles as potent and selective RORgt inhibitors

Structural highlights

6q6o is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

RORgammat is considered the master transcription factor for the development of Th17 cells that produce pro-inflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput FRET screen, we identified compound 1 as hit with promising lipE. Using structure-based drug design based on a number of X-ray co-crystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3. To improve the poor ADME properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents towards a polar, water rich area of the protein. This highly lipophilicity efficient modification ultimately led to the discovery of compound 14, a potent and selective inhibitor of RORgammat with good ADME properties and excellent in vivo pharmacokinetics. This compound showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology model in rats.

Structure-based and property-driven optimization of N-aryl imidazoles towards potent and selective oral RORgammat inhibitors.,Hoegenauer K, Kallen J, Jimenez-Nunez E, Strang R, Ertl P, Cooke NG, Hintermann S, Voegtle M, Betschart C, Mckay DJJ, Wagner J, Ottl J, Beerli C, Billich A, Dawson J, Kaupmann K, Streiff M, Gobeau N, Harlfinger S, Stringer R, Guntermann C J Med Chem. 2019 Nov 15. doi: 10.1021/acs.jmedchem.9b01291. PMID:31729873^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hoegenauer K, Kallen J, Jimenez-Nunez E, Strang R, Ertl P, Cooke NG, Hintermann S, Voegtle M, Betschart C, Mckay DJJ, Wagner J, Ottl J, Beerli C, Billich A, Dawson J, Kaupmann K, Streiff M, Gobeau N, Harlfinger S, Stringer R, Guntermann C. Structure-based and property-driven optimization of N-aryl imidazoles towards potent and selective oral RORgammat inhibitors. J Med Chem. 2019 Nov 15. doi: 10.1021/acs.jmedchem.9b01291. PMID:31729873 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01291

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6q6o"

Categories: Homo sapiens | Large Structures | Kallen J

@@ Line 3: / Line 3: @@
 <StructureSection load='6q6o' size='340' side='right'caption='[[6q6o]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6q6o]] 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=6Q6O OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q6O FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6q6o]] 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=6Q6O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Q6O FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CHD:CHOLIC+ACID'>CHD</scene>, <scene name='pdbligand=HKE:propan-2-yl+(2~{S})-2-[[2,6-bis(chloranyl)phenyl]-(furan-2-ylcarbonyl)amino]propanoate'>HKE</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]] 2.3&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6q6m|6q6m]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CHD:CHOLIC+ACID'>CHD</scene>, <scene name='pdbligand=HKE:propan-2-yl+(2~{S})-2-[[2,6-bis(chloranyl)phenyl]-(furan-2-ylcarbonyl)amino]propanoate'>HKE</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6q6o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q6o OCA], [https://pdbe.org/6q6o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6q6o RCSB], [https://www.ebi.ac.uk/pdbsum/6q6o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6q6o ProSAT]</span></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=6q6o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q6o OCA], [http://pdbe.org/6q6o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q6o RCSB], [http://www.ebi.ac.uk/pdbsum/6q6o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q6o ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Kallen, J]]
+[[Category: Kallen J]]
-[[Category: Inverse agonist]]
-[[Category: Ligand-binding domain]]
-[[Category: Nuclear hormone receptor]]
-[[Category: Transcription]]

6q6o

From Proteopedia

Current revision

RORCVAR2 (RORGT, 264-499) IN COMPLEX WITH COMPOUND 2 AT 2.3A: Identification of N-aryl imidazoles as potent and selective RORgt inhibitors

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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