4WQP

Crystal structure of RORc in complex with a benzyl sulfonamide inverse agonist

Summary for 4WQP

• Entry DOI: 10.2210/pdb4wqp/pdb
• Descriptor: Nuclear receptor ROR-gamma, VAL-GLU-ARG-LEU-GLN-ILE-PHE-GLN-HIS-LEU-HIS-PRO-ILE, N-[4-(4-acetylpiperazin-1-yl)benzyl]-N-(2-methylpropyl)-1-phenylmethanesulfonamide, ... (5 entities in total)
• Functional Keywords: nuclear receptor ligand binding domain, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : P51449
• Total number of polymer chains: 3
• Total formula weight: 64419.26

Authors

Boenig, G.,Hymowitz, S.G. (deposition date: 2014-10-22, release date: 2015-01-14, Last modification date: 2023-12-27)

Primary citation

Rene, O.,Fauber, B.P.,de Leon Boenig, G.,Burton, B.,Eidenschenk, C.,Everett, C.,Gobbi, A.,Hymowitz, S.G.,Johnson, A.R.,Kiefer, J.R.,Liimatta, M.,Lockey, P.,Norman, M.,Ouyang, W.,Wallweber, H.A.,Wong, H.
Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.
Acs Med.Chem.Lett., 6:276-281, 2015

PubMed Abstract: A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.

PubMed: 25815138
DOI: 10.1021/ml500420y

Experimental method

X-RAY DIFFRACTION (1.99 Å)