6D3N

Crystal structure of h4-1BB ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.212 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier.

Bitra, A.Doukov, T.Croft, M.Zajonc, D.M.

(2018) J Biol Chem 293: 9958-9969

  • DOI: https://doi.org/10.1074/jbc.RA118.003176
  • Primary Citation of Related Structures:  
    6CPR, 6CU0, 6D3N

  • PubMed Abstract: 

    Human (h)4-1BB (TNFRSF9 or CD137) is an inducible tumor necrosis factor receptor (TNFR) superfamily member that interacts with its cognate ligand h4-1BBL to promote T lymphocyte activation and proliferation. h4-1BB is currently being targeted with agonists in cancer immunotherapy. Here, we determined the crystal structures of unbound h4-1BBL and both WT h4-1BB and a dimerization-deficient h4-1BB mutant (C121S) in complex with h4-1BBL at resolutions between 2.7 and 3.2 Å. We observed that the structural arrangement of 4-1BBL, both unbound and in the complex, represents the canonical bell shape as seen in other similar TNF proteins and differs from the previously reported three-bladed propeller structure of 4-1BBL. We also found that the binding site for the receptor is at the crevice formed between two protomers of h4-1BBL, but that h4-1BB interacts predominantly with only one ligand protomer. Moreover, h4-1BBL lacked the conserved tyrosine residue in the DE loop that forms canonical interactions between other TNFR family molecules and their ligands, suggesting h4-1BBL engages h4-1BB through a distinct mechanism. Of note, we discovered that h4-1BB forms a disulfide-linked dimer because of the presence of an additional cysteine residue found in its cysteine-rich domain 4 (CRD4). As a result, h4-1BB dimerization, in addition to trimerization via h4-1BBL binding, could result in cross-linking of individual ligand-receptor complexes to form a 2D network that stimulates strong h4-1BB signaling. This work provides critical insights into the structural and functional properties of both h4-1BB and h4-1BBL and reveals that covalent receptor dimerization amplifies h4-1BB signaling.


  • Organizational Affiliation

    From the Division of Immune Regulation, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, California 92037.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tumor necrosis factor ligand superfamily member 9171Homo sapiensMutation(s): 0 
Gene Names: TNFSF9
UniProt & NIH Common Fund Data Resources
Find proteins for P41273 (Homo sapiens)
Explore P41273 
Go to UniProtKB:  P41273
PHAROS:  P41273
GTEx:  ENSG00000125657 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP41273
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GOL
Query on GOL

Download Ideal Coordinates CCD File 
B [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.212 
  • Space Group: H 3 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.167α = 90
b = 73.167β = 90
c = 162.814γ = 120
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
iMOSFLMdata reduction
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-09
    Type: Initial release
  • Version 1.1: 2018-07-11
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Refinement description