6CW6

Structure of alpha-GC[8,18] bound by CD1d and in complex with the Va14Vb8.2 TCR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

Starting Model: experimental
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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted PBSClick on this verticalbar to view detailsBest fitted PLMClick on this verticalbar to view detailsBest fitted NAGClick on this verticalbar to view details

This is version 2.2 of the entry. See complete history


Literature

A molecular switch in mouse CD1d modulates natural killer T cell activation by alpha-galactosylsphingamides.

Wang, J.Guillaume, J.Janssens, J.Remesh, S.G.Ying, G.Bitra, A.Van Calenbergh, S.Zajonc, D.M.

(2019) J Biol Chem 294: 14345-14356

  • DOI: https://doi.org/10.1074/jbc.RA119.009963
  • Primary Citation of Related Structures:  
    6C5M, 6C69, 6C6A, 6C6C, 6C6E, 6C6H, 6C6J, 6CW6, 6CW9, 6CWB, 6CX5, 6CX7, 6CX9, 6CXA, 6CXE, 6CXF, 6OJP

  • PubMed Abstract: 

    Type I natural killer T (NKT) cells are a population of innate like T lymphocytes that rapidly respond to α-GalCer presented by CD1d via the production of both pro- and anti-inflammatory cytokines. While developing novel α-GalCer analogs that were meant to be utilized as potential adjuvants because of their production of pro-inflammatory cytokines (Th1 skewers), we generated α-galactosylsphingamides (αGSA). Surprisingly, αGSAs are not potent antigens in vivo despite their strong T-cell receptor (TCR)-binding affinities. Here, using surface plasmon resonance (SPR), antigen presentation assays, and X-ray crystallography (yielding crystal structures of 19 different binary (CD1d-glycolipid) or ternary (CD1d-glycolipid-TCR) complexes at resolutions between 1.67 and 2.85 Å), we characterized the biochemical and structural details of αGSA recognition by murine NKT cells. We identified a molecular switch within murine (m)CD1d that modulates NKT cell activation by αGSAs. We found that the molecular switch involves a hydrogen bond interaction between Tyr-73 of mCD1d and the amide group oxygen of αGSAs. We further established that the length of the acyl chain controls the positioning of the amide group with respect to the molecular switch and works synergistically with Tyr-73 to control NKT cell activity. In conclusion, our findings reveal important mechanistic insights into the presentation and recognition of glycolipids with polar moieties in an otherwise apolar milieu. These observations may inform the development αGSAs as specific NKT cell antagonists to modulate immune responses.


  • Organizational Affiliation

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


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Antigen-presenting glycoprotein CD1d1285Mus musculusMutation(s): 0 
Gene Names: Cd1d1Cd1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11609 (Mus musculus)
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Go to UniProtKB:  P11609
IMPC:  MGI:107674
Entity Groups  
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UniProt GroupP11609
Glycosylation
Glycosylation Sites: 3Go to GlyGen: P11609-1
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-2-microglobulin99Mus musculusMutation(s): 0 
Gene Names: B2m
UniProt & NIH Common Fund Data Resources
Find proteins for P01887 (Mus musculus)
Explore P01887 
Go to UniProtKB:  P01887
IMPC:  MGI:88127
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UniProt GroupP01887
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Chimeric T cell antigen receptor alpha chain209Mus musculusHomo sapiens
This entity is chimeric
Mutation(s): 0 
Gene Names: Trav11Trav11dB2MHDCMA22P
UniProt
Find proteins for K7N5M3 (Homo sapiens)
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Go to UniProtKB:  K7N5M3
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UniProt GroupK7N5M3
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Chimeric T cell antigen receptor beta chain Vb8.2241Mus musculusHomo sapiens
This entity is chimeric
Mutation(s): 0 
UniProt
Find proteins for K7N5M4 (Homo sapiens)
Explore K7N5M4 
Go to UniProtKB:  K7N5M4
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UniProt GroupK7N5M4
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
E
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G21290RB
GlyCosmos:  G21290RB
GlyGen:  G21290RB
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.641α = 90
b = 190.354β = 90
c = 150.785γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted PBSClick on this verticalbar to view detailsBest fitted PLMClick on this verticalbar to view detailsBest fitted NAGClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-03
    Type: Initial release
  • Version 1.1: 2019-10-16
    Changes: Data collection, Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary
  • Version 2.2: 2024-11-20
    Changes: Structure summary