6FZU

RORGT (264-518;C455S) IN COMPLEX WITH THE FRAGMENT ("CPD-1") AND RIP140 PEPTIDE AT 1.80A

Summary for 6FZU

• Entry DOI: 10.2210/pdb6fzu/pdb
• Descriptor: Nuclear receptor ROR-gamma, Nuclear receptor-interacting protein 1, ~{N}-(3-chloranyl-4-ethoxy-phenyl)ethanamide, ... (4 entities in total)
• Functional Keywords: fbs, nuclear hormone receptor, ligand-binding domain, inverse agonist, signaling protein, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 64545.18

Authors

Kallen, J. (deposition date: 2018-03-15, release date: 2018-07-18, Last modification date: 2024-01-17)

Primary citation

Carcache, D.A.,Vulpetti, A.,Kallen, J.,Mattes, H.,Orain, D.,Stringer, R.,Vangrevelinghe, E.,Wolf, R.M.,Kaupmann, K.,Ottl, J.,Dawson, J.,Cooke, N.G.,Hoegenauer, K.,Billich, A.,Wagner, J.,Guntermann, C.,Hintermann, S.
Optimizing a Weakly Binding Fragment into a Potent ROR gamma t Inverse Agonist with Efficacy in an in Vivo Inflammation Model.
J. Med. Chem., 61:6724-6735, 2018

PubMed Abstract: The transcription factor RORγt 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 RORγt 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.

PubMed: 29990434
DOI: 10.1021/acs.jmedchem.8b00529

Experimental method

X-RAY DIFFRACTION (1.8 Å)