6TLT

ROR(gamma)t ligand binding domain in complex with desmosterol and allosteric ligand Glenmark


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

Cooperativity between the orthosteric and allosteric ligand binding sites of ROR gamma t.

de Vries, R.M.J.M.Meijer, F.A.Doveston, R.G.Leijten-van de Gevel, I.A.Brunsveld, L.

(2021) Proc Natl Acad Sci U S A 118

  • DOI: https://doi.org/10.1073/pnas.2021287118
  • Primary Citation of Related Structures:  
    6T4G, 6T4I, 6T4J, 6T4K, 6T4T, 6T4U, 6T4W, 6T4X, 6T4Y, 6T50, 6TLQ, 6TLT

  • PubMed Abstract: 

    Cooperative ligand binding is an important phenomenon in biological systems where ligand binding influences the binding of another ligand at an alternative site of the protein via an intramolecular network of interactions. The underlying mechanisms behind cooperative binding remain poorly understood, primarily due to the lack of structural data of these ternary complexes. Using time-resolved fluorescence resonance energy transfer (TR-FRET) studies, we show that cooperative ligand binding occurs for RORγt, a nuclear receptor associated with the pathogenesis of autoimmune diseases. To provide the crucial structural insights, we solved 12 crystal structures of RORγt simultaneously bound to various orthosteric and allosteric ligands. The presence of the orthosteric ligand induces a clamping motion of the allosteric pocket via helices 4 to 5. Additional molecular dynamics simulations revealed the unusual mechanism behind this clamping motion, with Ala355 shifting between helix 4 and 5. The orthosteric RORγt agonists regulate the conformation of Ala355, thereby stabilizing the conformation of the allosteric pocket and cooperatively enhancing the affinity of the allosteric inverse agonists.


  • Organizational Affiliation

    Laboratory of Chemical Biology, Department of Biomedical Engineering, Technische Universiteit Eindhoven, 5612 AZ Eindhoven, The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor ROR-gamma263Homo 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
MJE BindingDB:  6TLT IC50: min: 180, max: 547 (nM) from 5 assay(s)
EC50: 620 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 108.727α = 90
b = 108.727β = 90
c = 104.734γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
REFMACrefinement
PDB_EXTRACTdata extraction
DIALSdata reduction
STARANISOdata scaling
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Netherlands Organisation for Scientific ResearchNetherlands024.001.035
Netherlands Organisation for Scientific ResearchNetherlands016.150.366
European Union705188

Revision History  (Full details and data files)

  • Version 1.0: 2020-12-16
    Type: Initial release
  • Version 1.1: 2021-02-17
    Changes: Database references
  • Version 1.2: 2024-01-24
    Changes: Data collection, Database references, Refinement description