5W4V

Structure of RORgt bound to a tertiary alcohol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.384 
  • R-Value Work: 0.343 
  • R-Value Observed: 0.345 

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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, C, D, E
A, B, C, D, E, F
210Homo 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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
9WA BindingDB:  5W4V Kd: min: 5, max: 70 (nM) from 3 assay(s)
IC50: min: 57, max: 170 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.384 
  • R-Value Work: 0.343 
  • R-Value Observed: 0.345 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 133.118α = 90
b = 133.118β = 90
c = 181.843γ = 120
Software Package:
Software NamePurpose
SCALAdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-27
    Type: Initial release
  • Version 1.1: 2023-10-04
    Changes: Data collection, Database references, Refinement description