5W4R

Structure of RORgt bound to a tertiary alcohol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.196 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

6-Substituted quinolines as ROR gamma t inverse agonists.

Barbay, J.K.Cummings, M.D.Abad, M.Castro, G.Kreutter, K.D.Kummer, D.A.Maharoof, U.Milligan, C.Nishimura, R.Pierce, J.Schalk-Hihi, C.Spurlino, J.Tanis, V.M.Urbanski, M.Venkatesan, H.Wang, A.Woods, C.Wolin, R.Xue, X.Edwards, J.P.Fourie, A.M.Leonard, K.

(2017) Bioorg Med Chem Lett 27: 5277-5283

  • DOI: https://doi.org/10.1016/j.bmcl.2017.10.027
  • Primary Citation of Related Structures:  
    5W4R, 5W4V

  • PubMed Abstract: 

    We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). The synthesis of this class of RORγt modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a RORγt-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORγt ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact.


  • Organizational Affiliation

    Discovery Immunology, Janssen Research and Development, LLC, Welsh and McKean Roads, Spring House, PA 19477, United States. Electronic address: kbarbay@its.jnj.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor ROR-gamma
A, B
217Homo 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
9WD
Query on 9WD

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
1-{4-[(R)-(4-chloro-2-methoxy-3-{[4-(1H-pyrazol-1-yl)phenyl]methyl}quinolin-6-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl]piperidin-1-yl}ethan-1-one
C32 H33 Cl N6 O3
MAJOOHMQVBMIGI-JGCGQSQUSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
9WD BindingDB:  5W4R Kd: min: 18, max: 33 (nM) from 3 assay(s)
IC50: min: 46, max: 59 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.196 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 97.361α = 90
b = 97.361β = 90
c = 128.218γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-12-27 
  • Deposition Author(s): Spurlino, J.

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-27
    Type: Initial release
  • Version 1.1: 2024-03-13
    Changes: Advisory, Data collection, Database references