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4nb6

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Crystal structure of the ligand binding domain of RORC with T0901317

Structural highlights

4nb6 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 2.85Å
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

The structure-activity relationships of T0901317 analogs were explored as RORc inverse agonists using the principles of property- and structure-based drug design. An X-ray co-crystal structure of T0901317 and RORc was obtained and provided molecular insight into why T0901317 functioned as an inverse agonist of RORc; whereas, the same ligand functioned as an agonist of FXR, LXR, and PXR. The structural data was also used to design inhibitors with improved RORc biochemical and cellular activities. The improved inhibitors possessed enhanced selectivity profiles (rationalized using the X-ray crystallographic data) against other nuclear receptors.

Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc.,Fauber BP, de Leon Boenig G, Burton B, Eidenschenk C, Everett C, Gobbi A, Hymowitz SG, Johnson AR, Liimatta M, Lockey P, Norman M, Ouyang W, Rene O, Wong H Bioorg Med Chem Lett. 2013 Dec 15;23(24):6604-9. doi: 10.1016/j.bmcl.2013.10.054., Epub 2013 Nov 4. PMID:24239186^[1]

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

References

↑ Fauber BP, de Leon Boenig G, Burton B, Eidenschenk C, Everett C, Gobbi A, Hymowitz SG, Johnson AR, Liimatta M, Lockey P, Norman M, Ouyang W, Rene O, Wong H. Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc. Bioorg Med Chem Lett. 2013 Dec 15;23(24):6604-9. doi: 10.1016/j.bmcl.2013.10.054., Epub 2013 Nov 4. PMID:24239186 doi:http://dx.doi.org/10.1016/j.bmcl.2013.10.054