The crystal structure of human CD1d with and without -galactosylceramide

Michael Koch^1, 8, Victoria S Stronge^2, 8, Dawn Shepherd², Stephan D Gadola³, Bini Mathew⁴, Gerd Ritter⁵, Alan R Fersht⁶, Gurdyal S Besra⁷, Richard R Schmidt⁴, E Yvonne Jones¹ & Vincenzo Cerundolo²

¹  Cancer Research UK Receptor Structure Research Group, The Henry Wellcome Building for Genomic Medicine, Roosevelt Drive, Headington, Oxford OX3 7BN, UK.

²  Cancer Research UK Tumor Immunology Group, The Weatherall Institute of Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.

³  Department of Rheumatology and Clinical Immunology, University of Berne, Inselspital, PKT2 D584, Berne CH-3010, Switzerland.

⁴  Department of Chemistry, University of Konstanz, D-78457 Konstanz, Germany.

⁵  Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.

⁶  Medical Research Council Centre for Protein Engineering, Cambridge, CB2 2QH, UK.

⁷  School of Biosciences, The University of Birmingham, Birmingham B 15 2TT, UK.

⁸  These authors contributed equally to this work.

The glycolipid -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 -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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