4WPF

Crystal structure of RORc in complex with a phenyl sulfonamide agonist

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.180 

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Literature

Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.

Rene, O., Fauber, B.P., de Leon Boenig, G., Burton, B., Eidenschenk, C., Everett, C., Gobbi, A., Hymowitz, S.G., Johnson, A.R., Kiefer, J.R., Liimatta, M., Lockey, P., Norman, M., Ouyang, W., Wallweber, H.A., Wong, H.

(2015) ACS Med Chem Lett 6: 276-281

  • DOI: https://doi.org/10.1021/ml500420y
  • Primary Citation of Related Structures:  
    4WPF, 4WQP

  • PubMed Abstract: 

    A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.

    • Organizational Affiliation: 

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor ROR-gammaA,
C [auth D]		264Homo sapiensMutation(s): 0 
Gene Names: RORC, NR1F3, RORG, RZRG
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

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
RHKILHRLLQEGSPSB,
D [auth E]		11Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3SN
Query on 3SN
Download Ideal Coordinates CCD File 
E [auth A],
F [auth D]		N-[4-(4-acetylpiperazin-1-yl)-2-fluorobenzyl]-N-cyclobutylbenzenesulfonamide
C23 H28 F N3 O3 S
PIGCNHMXDYACOO-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3SN BindingDB:  4WPF IC50: min: 249, max: 250 (nM) from 2 assay(s)
EC50: 69 (nM) from 1 assay(s)
Binding MOAD:  4WPF IC50: 250 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.180 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 61.692α = 90
b = 61.692β = 90
c = 155.232γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
SCALEPACKdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-01-14
    Type: Initial release
  • Version 1.1: 2015-04-15
    Changes: Database references
  • Version 1.2: 2023-12-27
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy