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5aph

From Proteopedia

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Ligand complex of RORg LBD

Structural highlights

5aph is a 2 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 1.54Å
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, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORgamma), has been identified as the master regulator of T-helper 17 (TH 17) cell function and development, making it an attractive target for the treatment of autoimmune diseases. Validation for this target comes from antibodies targeting interleukin-17 (IL-17), the signature cytokine produced by TH 17 cells, which have shown impressive results in clinical trials. Through focused screening of our compound collection, we identified a series of N-sulfonylated benzoxazepines, which displayed micromolar affinity for the RORgamma ligand-binding domain (LBD) in a radioligand binding assay. Optimization of these initial hits resulted in potent binders, which dose-dependently decreased the ability of the RORgamma-LBD to interact with a peptide derived from steroid receptor coactivator 1, and inhibited the release of IL-17 secretion from isolated and cultured human TH 17 cells with nanomolar potency. A cocrystal structure of inverse agonist 15 (2-chloro-6-fluoro-N-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}-2,3,4,5-tetrahydro- 1,4-benzoxazepin-7-yl)benzamide) bound to the RORgamma-LBD illustrated that both hydrophobic interactions, leading to an induced fit around the substituted benzamide moiety of 15, as well as a hydrogen bond from the amide NH to His479 seemed to be important for the mechanism of action. This structure is compared with the structure of agonist 25 (N-(2-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxaze pin-6-amine ) and structures of other known RORgamma modulators.

Benzoxazepines Achieve Potent Suppression of IL-17 Release in Human T-Helper 17 (T 17) Cells through an Induced-Fit Binding Mode to the Nuclear Receptor RORgamma.,Olsson RI, Xue Y, von Berg S, Aagaard A, McPheat J, Hansson EL, Bernstrom J, Hansson P, Jirholt J, Grindebacke H, Leffler A, Chen R, Xiong Y, Ge H, Hansson TG, Narjes F ChemMedChem. 2015 Nov 10. doi: 10.1002/cmdc.201500432. PMID:26553345^[1]

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

References

↑ Olsson RI, Xue Y, von Berg S, Aagaard A, McPheat J, Hansson EL, Bernstrom J, Hansson P, Jirholt J, Grindebacke H, Leffler A, Chen R, Xiong Y, Ge H, Hansson TG, Narjes F. Benzoxazepines Achieve Potent Suppression of IL-17 Release in Human T-Helper 17 (T 17) Cells through an Induced-Fit Binding Mode to the Nuclear Receptor RORgamma. ChemMedChem. 2015 Nov 10. doi: 10.1002/cmdc.201500432. PMID:26553345 doi:http://dx.doi.org/10.1002/cmdc.201500432

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/5aph"

Categories: Homo sapiens | Large Structures | Aagaard A | Narjes F | Xue Y

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5aph]] 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=5APH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5APH FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=VYI:N-(2-FLUOROPHENYL)-4-[(4-FLUOROPHENYL)SULFONYL]-2,3,4,5-TETRAHYDRO-1,4-BENZOXAZEPIN-6-AMINE'>VYI</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]] 1.54&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=VYI:N-(2-FLUOROPHENYL)-4-[(4-FLUOROPHENYL)SULFONYL]-2,3,4,5-TETRAHYDRO-1,4-BENZOXAZEPIN-6-AMINE'>VYI</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=5aph FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aph OCA], [https://pdbe.org/5aph PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aph RCSB], [https://www.ebi.ac.uk/pdbsum/5aph PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aph ProSAT]</span></td></tr>
 </table>

5aph

From Proteopedia

Current revision

Ligand complex of RORg LBD

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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