PDBsum entry 6fgq

Transcription

PDB id: 6fgq

Contents

Protein chains

229 a.a.

214 a.a.

Ligands

D9N ×2

Waters ×141

PDB id:

6fgq

Name:

Transcription

Title:

Ligand complex of rorg lbd

Structure:

Nuclear receptor ror-gamma. Chain: a, b. 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: 562

Resolution:

2.37Å R-factor: 0.214 R-free: 0.242

Authors:

Y.Xue,A.Aagaard,F.Narjes

Key ref:

F.Narjes et al. (2018). Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design. J Med Chem, 61, 7796-7813. PubMed id: 30095900 DOI: 10.1021/acs.jmedchem.8b00783

Date:

11-Jan-18 Release date: 22-Aug-18

Protein chain

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

Seq: 518 a.a.

Struc: 229 a.a.*

Protein chain

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

Seq: 518 a.a.

Struc: 214 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.?

DOI no: 10.1021/acs.jmedchem.8b00783

J Med Chem 61:7796-7813 (2018)

PubMed id: 30095900

Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design.

F.Narjes, Y.Xue, S.von Berg, J.Malmberg, A.Llinas, R.I.Olsson, J.Jirholt, H.Grindebacke, A.Leffler, N.Hossain, M.Lepistö, L.Thunberg, H.Leek, A.Aagaard, J.McPheat, E.L.Hansson, E.Bäck, S.Tångefjord, R.Chen, Y.Xiong, G.Hongbin, T.G.Hansson.

ABSTRACT

Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of T_H17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-T_H17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.