6CW9

Structure of alpha-GC[8,16P] bound by CD1d and in complex with the Va14Vb8.2 TCR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 

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Ligand Structure Quality Assessment 


This is version 2.1 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
Chimeric T cell antigen receptor alpha chain. Va14,Va24,Ja18A [auth C]203Mus musculusMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Chimeric T cell antigen receptor beta chain Vb8.2, vb11B [auth D]239Mus musculusMutation(s): 0 
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Antigen-presenting glycoprotein CD1d1C [auth A]274Mus musculusMutation(s): 0 
Gene Names: Cd1d1mCG_3074
UniProt & NIH Common Fund Data Resources
Find proteins for P11609 (Mus musculus)
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Go to UniProtKB:  P11609
IMPC:  MGI:107674
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UniProt GroupP11609
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-2-microglobulinD [auth B]97Mus 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
Oligosaccharides

Help

Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 6
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
F
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G21290RB
GlyCosmos:  G21290RB
GlyGen:  G21290RB
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7LM
Query on 7LM

Download Ideal Coordinates CCD File 
I [auth A]N-[(2S,3S,4R)-1-(alpha-D-galactopyranosyloxy)-3,4-dihydroxy-16-phenylhexadecan-2-yl]octanamide
C36 H63 N O9
YDGPBAWHWVHKQP-QNAIHFNASA-N
PLM
Query on PLM

Download Ideal Coordinates CCD File 
H [auth A]PALMITIC ACID
C16 H32 O2
IPCSVZSSVZVIGE-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
G [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 79.223α = 90
b = 192.026β = 90
c = 151.113γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
SCALEPACKdata scaling
PDB_EXTRACTdata extraction
HKL-2000data 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: 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