4ZJW

RORgamma in complex with inverse agonist 16


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of biaryl carboxylamides as potent ROR gamma inverse agonists.

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

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

  • DOI: https://doi.org/10.1016/j.bmcl.2015.05.026
  • Primary Citation of Related Structures:  
    4ZJR, 4ZJW

  • PubMed 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.


  • Organizational Affiliation

    Chemical and Molecular Therapeutics, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, United States. Electronic address: jianhua.chao@gmail.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor ROR-gamma
A, B
225Homo sapiensMutation(s): 0 
Gene Names: RORCNR1F3RORGRZRG
UniProt & NIH Common Fund Data Resources
Find proteins for P51449 (Homo sapiens)
Explore P51449 
Go to UniProtKB:  P51449
PHAROS:  P51449
GTEx:  ENSG00000143365 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51449
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4P1
Query on 4P1

Download Ideal Coordinates CCD File 
C [auth A]4-chloro-3-[1-(2-chloro-6-fluorobenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl]-N-methylbenzamide
C24 H19 Cl2 F N2 O2
NWECRSKQCPBSPW-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4P1 Binding MOAD:  4ZJW IC50: 100 (nM) from 1 assay(s)
BindingDB:  4ZJW IC50: 100 (nM) from 1 assay(s)
EC50: 200 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 125.586α = 90
b = 56.313β = 124.66
c = 79.517γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
SCALAdata scaling
PDB_EXTRACTdata extraction
Cootmodel building
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-06-17
    Type: Initial release
  • Version 1.1: 2015-06-24
    Changes: Data collection
  • Version 1.2: 2017-11-01
    Changes: Author supporting evidence, Database references, Derived calculations, Source and taxonomy
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Refinement description