Structural studies unravel the active conformation of apo RORÎ³t nuclear receptor and a common inverse agonism of two diverse classes of RORÎ³t inhibitors.

Li, Xiang; Anderson, Marie; Collin, Delphine; Muegge, Ingo; Wan, John; Brennan, Debra; Kugler, Stanley; Terenzio, Donna; Kennedy, Charles; Lin, Siqi; Labadia, Mark E; Cook, Brian; Hughes, Robert; Farrow, Neil A

Li, Xiang; Anderson, Marie; Collin, Delphine; Muegge, Ingo; Wan, John; Brennan, Debra; Kugler, Stanley; Terenzio, Donna; Kennedy, Charles; Lin, Siqi; Labadia, Mark E; Cook, Brian; Hughes, Robert; Farrow, Neil A.

Affiliation

Li X; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368. Electronic address: xiang.li@boehringer-ingelheim.com.
Anderson M; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Collin D; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Muegge I; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Wan J; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Brennan D; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Kugler S; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Terenzio D; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Kennedy C; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Lin S; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Labadia ME; Immunology and Respiratory Diseases, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877-0368.
Cook B; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Hughes R; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.
Farrow NA; Departments of Small Molecule Discovery Research, Ridgefield, Connecticut 06877-0368.

J Biol Chem ; 292(28): 11618-11630, 2017 07 14.

Article in En | MEDLINE | ID: mdl-28546429

Subject(s)

Anti-Inflammatory Agents, Non-Steroidal/pharmacology; Drug Inverse Agonism; Models, Molecular; Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors; Anti-Inflammatory Agents, Non-Steroidal/chemistry; Anti-Inflammatory Agents, Non-Steroidal/metabolism; Apoproteins/antagonists & inhibitors; Apoproteins/chemistry; Apoproteins/genetics; Apoproteins/metabolism; Binding Sites; Binding, Competitive; Cells, Cultured; Genes, Reporter/drug effects; HEK293 Cells; Humans; Interleukin-17/antagonists & inhibitors; Interleukin-17/metabolism; Ligands; Molecular Conformation; Nuclear Receptor Subfamily 1, Group F, Member 3/chemistry; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism; Peptide Fragments/antagonists & inhibitors; Peptide Fragments/chemistry; Peptide Fragments/genetics; Peptide Fragments/metabolism; Phenylalanine/analogs & derivatives; Phenylalanine/chemistry; Phenylalanine/metabolism; Phenylalanine/pharmacology; Phenylurea Compounds/chemistry; Phenylurea Compounds/metabolism; Phenylurea Compounds/pharmacology; Protein Conformation; Protein Interaction Domains and Motifs; Protein Refolding; Protein Stability; Recombinant Fusion Proteins/chemistry; Recombinant Fusion Proteins/metabolism; Th17 Cells/drug effects; Th17 Cells/metabolism

Key words

crystal structure; drug discovery; nuclear magnetic resonance (NMR); nuclear receptor; protein drug interaction; retinoid acid receptor-related orphan receptor Î³t (RORÎ³t); x-ray crystallography

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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Models, Molecular / Anti-Inflammatory Agents, Non-Steroidal / Drug Inverse Agonism / Nuclear Receptor Subfamily 1, Group F, Member 3 Type of study: Prognostic_studies Language: En Journal: J Biol Chem Year: 2017 Type: Article

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