PMID: 16537470

 

    Legend: Gene, Sites

Title : Design of natural killer T cell activators: structure and function of a microbial glycosphingolipid bound to mouse CD1d

Abstract :
  1. Natural killer T (NKT) cells provide an innate-type immune response upon T cell receptor interaction with CD1d-presented antigens
  2. We demonstrate through equilibrium tetramer binding and antigen presentation assays with Valpha14 i-positive NKT cell hybridomas that the Sphingomonas glycolipid alpha-galacturonosyl ceramide (GalA-GSL) is a NKT cell agonist that is significantly weaker than alpha-galactosylceramide (alpha-GalCer), the most potent known NKT agonist
  3. For GalA-GSL, a shorter fatty acyl chain , an absence of the 4-OH on the sphingosine tail and a 6'-COOH group on the galactose moiety account for its observed antigenic potency
  4. We further determined the crystal structure of mCD1d in complex with GalA-GSL at 1.8-A resolution
  5. The overall binding mode of GalA-GSL to mCD1d is similar to that of the short-chain alpha-GalCer ligand PBS-25, but its sphinganine chain is more deeply inserted into the F' pocket due to alternate hydrogen-bonding interactions between the sphinganine 3-OH with Asp-80
  6. Subsequently, a slight lateral shift (>1 A) of the galacturonosyl head group is noted at the CD1 surface compared with the galactose of alpha-GalCer
  7. Because the relatively short C(14) fatty acid of GalA-GSL does not fully occupy the A' pocket, a spacer lipid is found that stabilizes this pocket
  8. The lipid spacer was identified by GC/MS as a mixture of saturated and monounsaturated palmitic acid ( C(16) )
  9. Comparison of available crystal structures of alpha-anomeric glycosphingolipids now sheds light on the structural basis of their differential antigenic potency and has led to the design and synthesis of NKT cell agonists with enhanced cell-based stimulatory activities compared with alpha-GalCer
Output (sent_index, trigger, protein, sugar, site):
  • 3. chain, , chain, the galactose moiety, -
Output(Part-Of) (sent_index, protein, site):
  • 3. chain, tail
*Output_Site_Fusion* (sent_index, protein, sugar, site):

 

 

Protein NCBI ID SENTENCE INDEX
mCD1d 111334 5
structure of mCD1d 111334 4
Valpha14 111622 2
CD1 111334 6