PDBsum entry 4zjw

Transcription

PDB id: 4zjw

Contents

Protein chains

219 a.a.

Ligands

4P1

Waters ×70

PDB id:

4zjw

Name:

Transcription

Title:

Rorgamma in complex with inverse agonist 16

Structure:

Nuclear receptor ror-gamma. Chain: a, b. Fragment: ligand binding domain (unp residues 265-487). Synonym: nuclear receptor rzr-gamma,nuclear receptor subfamily 1 group f member 3,rar-related orphan receptor c,retinoid-related orphan receptor-gamma. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: rorc, nr1f3, rorg, rzrg. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.50Å R-factor: 0.193 R-free: 0.250

Authors:

D.J.Marcotte

Key ref:

J.Chao et al. (2015). Discovery of biaryl carboxylamides as potent RORγ inverse agonists. Bioorg Med Chem Lett, 25, 2991-2997. PubMed id: 26048806 DOI: 10.1016/j.bmcl.2015.05.026

Date:

29-Apr-15 Release date: 17-Jun-15

Protein chains

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

Seq: 518 a.a.

Struc: 219 a.a.

DOI no: 10.1016/j.bmcl.2015.05.026

Bioorg Med Chem Lett 25:2991-2997 (2015)

PubMed id: 26048806

Discovery of biaryl carboxylamides as potent RORγ inverse agonists.

J.Chao, I.Enyedy, K.Van Vloten, D.Marcotte, K.Guertin, R.Hutchings, N.Powell, H.Jones, T.Bohnert, C.C.Peng, L.Silvian, V.S.Hong, K.Little, D.Banerjee, L.Peng, A.Taveras, J.L.Viney, J.Fontenot.

ABSTRACT

RORγt is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORγ activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORγ inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with RORγ protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORγ inverse agonists, with demonstrated oral bioavailability in rodents.