6MJ4

Crystal structure of MCD1D/INKTCR TERNARY COMPLEX bound to glycolipid (XXW)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.186 

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This is version 2.1 of the entry. See complete history


Literature

4"-O-Alkylated alpha-Galactosylceramide Analogues as iNKT-Cell Antigens: Synthetic, Biological, and Structural Studies.

Janssens, J.Bitra, A.Wang, J.Decruy, T.Venken, K.van der Eycken, J.Elewaut, D.Zajonc, D.M.van Calenbergh, S.

(2019) ChemMedChem 14: 147-168

  • DOI: https://doi.org/10.1002/cmdc.201800649
  • Primary Citation of Related Structures:  
    6MIV, 6MIY, 6MJ4, 6MJ6, 6MJA, 6MJI, 6MJJ, 6MJQ

  • PubMed Abstract: 

    Invariant natural killer T-cells (iNKT) are a glycolipid-responsive subset of T-lymphocytes that fulfill a pivotal role in the immune system. The archetypical synthetic glycolipid, α-galactosylceramide (α-GalCer), whose molecular framework is inspired by a group of amphiphilic natural products, remains the most studied antigen for iNKT-cells. Nonetheless, the potential of α-GalCer as an immunostimulating agent is compromised by the fact that this glycolipid elicits simultaneous secretion of Th1- and Th2-cytokines. This has incited medicinal chemistry efforts to identify analogues that are able to perturb the Th1/Th2 balance. In this work, we present the synthesis of an extensive set of 4"-O-alkylated α-GalCer analogues, which were evaluated in vivo for their cytokine induction. We have found that conversion of the 4"-OH group to ether moieties decreases the immunogenic potential in mice relative to α-GalCer. Yet, the benzyl-modified glycolipids are able to produce a distinct pro-inflammatory immune response. The crystal structures suggest an extra hydrophobic interaction between the benzyl moiety and the α2-helix of CD1d.


  • Organizational Affiliation

    Laboratory for Medicinal Chemistry, Department of Pharmaceutics (FFW), Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
T cell receptor alpha variable 11,T cell receptor alpha variable 11,T cell receptor alpha joining 18,Human nkt tcr alpha chain, chimeric proteinA [auth C]209Mus musculusHomo sapiensMutation(s): 0 
Gene Names: Trav11Trav11dTraj18B2MHDCMA22P
UniProt
Find proteins for A0A0B4J1J9 (Mus musculus)
Explore A0A0B4J1J9 
Go to UniProtKB:  A0A0B4J1J9
Find proteins for K7N5M3 (Homo sapiens)
Explore K7N5M3 
Go to UniProtKB:  K7N5M3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsK7N5M3A0A0B4J1J9
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-chain,T cell receptor chain,T cell receptor beta constant 2, CHIMERIC PROTEINB [auth D]241Mus musculusHomo sapiensMutation(s): 2 
UniProt & NIH Common Fund Data Resources
Find proteins for A0N8J3 (Mus musculus)
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Go to UniProtKB:  A0N8J3
Find proteins for A2NTY6 (Mus musculus)
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Go to UniProtKB:  A2NTY6
Find proteins for A0A5B9 (Homo sapiens)
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Go to UniProtKB:  A0A5B9
PHAROS:  A0A5B9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsA0N8J3A0A5B9A2NTY6
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Antigen-presenting glycoprotein CD1d1C [auth A]285Mus musculusMutation(s): 0 
Gene Names: Cd1d1mCG_3074
UniProt & NIH Common Fund Data Resources
Find proteins for P11609 (Mus musculus)
Explore P11609 
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]99Mus 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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
JTG
Query on JTG

Download Ideal Coordinates CCD File 
O [auth A]N-[(2S,3S,4R)-3,4-dihydroxy-1-{[4-O-(prop-2-en-1-yl)-alpha-D-galactopyranosyl]oxy}octadecan-2-yl]hexacosanamide
C53 H103 N O9
ALFONRPZUQLTFA-BDHLTHOMSA-N
NAG
Query on NAG

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N [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
GOL
Query on GOL

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G [auth C]
H [auth C]
I [auth C]
J [auth C]
L [auth A]
G [auth C],
H [auth C],
I [auth C],
J [auth C],
L [auth A],
M [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
K [auth D]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.186 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.948α = 90
b = 190.723β = 90
c = 151.145γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data scaling
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-01-09
    Type: Initial release
  • Version 1.1: 2019-01-16
    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: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary