6g05
RORGT (264-518;C455S) IN COMPLEX WITH INVERSE AGONIST "CPD-2" AND RIP140 PEPTIDE AT 1.90A
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. [NRIP1_HUMAN] Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1. Also modulates transcriptional repression by nuclear hormone receptors.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe transcription factor RORgammat is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORgammat inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism. In contrast to other reported inverse agonists, there is no direct interaction or displacement of helix 12 observed in the crystal structure. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats. Optimizing a weakly binding fragment into a potent RORgammat inverse agonist with efficacy in an in vivo inflammation model.,Carcache D, Vulpetti A, Kallen J, Mattes H, Orain D, Stringer R, Vangrevelinghe E, Wolf RM, Kaupmann K, Ottl J, Dawson King J, Cooke NG, Hoegenauer K, Billich A, Wagner J, Guntermann C, Hintermann S J Med Chem. 2018 Jul 10. doi: 10.1021/acs.jmedchem.8b00529. PMID:29990434[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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