The glycolipid α-galactosylceramide binds with high affinity to CD1d and stimulates natural killer T cells. Here we report the crystal structure of human CD1d in complex with synthetic α-galactosylceramide at a resolution of 3.0 Å. The structure shows a tightly fit lipid in the CD1d binding groove, with the sphingosine chain bound in the C′ pocket and the longer acyl chain anchored in the A′ pocket. We also present the CD1d structure without lipid, which has a more open conformation of the binding groove, suggesting a dual conformation of CD1d in which the 'open' conformation is more able to load lipids. These structures provide clues as to how CD1 molecules load glycolipids as well as data to guide the design of new therapeutic agents.
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We thank R. Esnouf for help with the program VOLUMES and figures; J. Grimes and P. Salgado for assistance with crystallographic programs; D. Stuart for discussions; K. Harlos and the staff of the European Synchrotron Radiation Facility and European Molecular Biology Laboratory (Grenoble, France) for assistance with X-ray data collection. We acknowledge use of crystallization facilities provided by the Medical Research Council–funded Oxford Protein Production Facility and The European Commission Integrated Programme (SPINE; QLRT-2001-00988). Supported by Cancer Research UK (C399-A2291 to V.C., C375-A2320 to E.Y.J. and C399/A3213 to V.S.S.), the US Cancer Research Institute, the UK Medical Research Council (M.K.) and Overseas Research Scheme (V.S.S.).
The authors declare no competing financial interests.
The sugar head-group of the α-GalCer. (PDF 137 kb)
Packing of the hCD1d molecules within the crystal lattice. (PDF 131 kb)
FPLC profile of hCD1d-β2M refolding reactions in the presence and absence of α-GalCer. (PDF 86 kb)
Omit maps for the binding grooves of the two hCD1d molecules. (PDF 193 kb)
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Koch, M., Stronge, V., Shepherd, D. et al. The crystal structure of human CD1d with and without α-galactosylceramide. Nat Immunol 6, 819–826 (2005). https://doi.org/10.1038/ni1225
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