5C4S

Identification of a Novel Allosteric Binding Site for RORgt Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.226 

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Ligand Structure Quality Assessment 


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Literature

Identification of an allosteric binding site for ROR gamma t inhibition.

Scheepstra, M.Leysen, S.van Almen, G.C.Miller, J.R.Piesvaux, J.Kutilek, V.van Eenennaam, H.Zhang, H.Barr, K.Nagpal, S.Soisson, S.M.Kornienko, M.Wiley, K.Elsen, N.Sharma, S.Correll, C.C.Trotter, B.W.van der Stelt, M.Oubrie, A.Ottmann, C.Parthasarathy, G.Brunsveld, L.

(2015) Nat Commun 6: 8833-8833

  • DOI: https://doi.org/10.1038/ncomms9833
  • Primary Citation of Related Structures:  
    4YPQ, 5C4O, 5C4S, 5C4T, 5C4U

  • PubMed Abstract: 

    RORγt is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORγt. Co-crystallization of the ligand binding domain (LBD) of RORγt with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORγt LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORγt function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORγt ligands. This brings forward an approach to target RORγt for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors.


  • Organizational Affiliation

    Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute of Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, Eindhoven 5600MB, The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor ROR-gamma241Homo sapiensMutation(s): 1 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4Y5
Query on 4Y5

Download Ideal Coordinates CCD File 
B [auth A]4-{1-[2-chloro-6-(trifluoromethyl)benzoyl]-4-fluoro-1H-indazol-3-yl}-3-fluorobenzoic acid
C22 H10 Cl F5 N2 O3
PFVOSXMQCIFOSO-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4Y5 Binding MOAD:  5C4S IC50: 3.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.226 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 108.45α = 90
b = 108.45β = 90
c = 106.3γ = 120
Software Package:
Software NamePurpose
BUSTERrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-16
    Type: Initial release
  • Version 1.1: 2024-03-06
    Changes: Data collection, Database references, Derived calculations