CD1 molecules are MHC class-I-like glycoproteins that bind lipid-based antigens, but the binding mechanisms that are used by CD1 molecules to accommodate lipid antigens that seem to be too large for the binding groove have remained unclear. Gadola et al., reporting in Nature Immunology, describe the crystal structures of human CD1B complexed to glycolipid antigens. These new structures reveal that the binding groove is more complex than was previously supposed, which helps to explain the ability of CD1 molecules to bind long lipid chains.

Gadola et al. developed an in vitro system for refolding denatured CD1B molecules in the presence of defined glycolipids. The complexes produced were cystallized and the structures analysed in detail. Compared with MHC class I, the binding groove of CD1B is a complex maze of interconnecting pockets and tunnels — three distinct pockets, named A′, C′ and F′, were defined, as well as a connecting tunnel, termed T′. CD1B can bind long lipid chains by accommodating alkyl chains of up to 70 carbons in length in a superchannel formed by the connection of A′, T′ and F′. The C′ pocket can accommodate shorter alkyl chains of ∼16 carbons. An exit portal for the C′ pocket, located below the α2 helix, indicates that longer chains might also be accommodated. These structures show how CD1B can adapt to bind lipid ligands of various sizes.