PDBsum entry 5apj

Transcription

PDB id: 5apj

Contents

Protein chain

250 a.a.

Ligands

LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-ASP-SER

76E

Metals

_NA

Waters ×203

PDB id:

5apj

Name:

Transcription

Title:

Ligand complex of rorg lbd

Structure:

Nuclear receptor ror-gamma. Chain: a. Fragment: ligand binding domain, unp residues 265-507. Synonym: nuclear receptor rzr-gamma, nuclear receptor subfamily 1 group f member 3, rar-related orphan receptor c, retinoid-related orphan receptor-gamma, rorg. Engineered: yes. Nuclear receptor coactivator 2. Chain: c.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

2.08Å R-factor: 0.200 R-free: 0.238

Authors:

Y.Xue,A.Aagaard,F.Narjes

Key ref:

R.I.Olsson et al. (2016). Benzoxazepines Achieve Potent Suppression of IL-17 Release in Human T-Helper 17 (TH 17) Cells through an Induced-Fit Binding Mode to the Nuclear Receptor RORγ. Chemmedchem, 11, 207-216. PubMed id: 26553345 DOI: 10.1002/cmdc.201500432

Date:

16-Sep-15 Release date: 25-Nov-15

Protein chain

P51449  (RORG_HUMAN) -  Nuclear receptor ROR-gamma from Homo sapiens

Seq: 518 a.a.

Struc: 250 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

DOI no: 10.1002/cmdc.201500432

Chemmedchem 11:207-216 (2016)

PubMed id: 26553345

Benzoxazepines Achieve Potent Suppression of IL-17 Release in Human T-Helper 17 (TH 17) Cells through an Induced-Fit Binding Mode to the Nuclear Receptor RORγ.

R.I.Olsson, Y.Xue, S.von Berg, A.Aagaard, J.McPheat, E.L.Hansson, J.Bernström, P.Hansson, J.Jirholt, H.Grindebacke, A.Leffler, R.Chen, Y.Xiong, H.Ge, T.G.Hansson, F.Narjes.

ABSTRACT

RORγt, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORγ), has been identified as the master regulator of T-helper 17 (TH 17) cell function and development, making it an attractive target for the treatment of autoimmune diseases. Validation for this target comes from antibodies targeting interleukin-17 (IL-17), the signature cytokine produced by TH 17 cells, which have shown impressive results in clinical trials. Through focused screening of our compound collection, we identified a series of N-sulfonylated benzoxazepines, which displayed micromolar affinity for the RORγ ligand-binding domain (LBD) in a radioligand binding assay. Optimization of these initial hits resulted in potent binders, which dose-dependently decreased the ability of the RORγ-LBD to interact with a peptide derived from steroid receptor coactivator 1, and inhibited the release of IL-17 secretion from isolated and cultured human TH 17 cells with nanomolar potency. A cocrystal structure of inverse agonist 15 (2-chloro-6-fluoro-N-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide) bound to the RORγ-LBD illustrated that both hydrophobic interactions, leading to an induced fit around the substituted benzamide moiety of 15, as well as a hydrogen bond from the amide NH to His479 seemed to be important for the mechanism of action. This structure is compared with the structure of agonist 25 (N-(2-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-6-amine ) and structures of other known RORγ modulators.