 |
PDBsum entry 4zjr
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
4zjr
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Transcription
|
|
|
Title:
|
|
Rorgamma in complex with inverse agonist 48
|
|
Structure:
|
|
Nuclear receptor ror-gamma. Chain: a, b, c, d. 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:
|
|
|
2.70Å
|
R-factor:
|
0.176
|
R-free:
|
0.223
|
|
|
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:
DOI:
|
|
|
Date:
|
|
|
29-Apr-15
|
Release date:
|
17-Jun-15
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P51449
(RORG_HUMAN) -
Nuclear receptor ROR-gamma from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
518 a.a.
217 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
Bioorg Med Chem Lett
25:2991-2997
(2015)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
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.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
