Ligand-responsive groove remodelling in human and macaque CD1d reveals a conserved MHC-like gating mechanism

Abstract

CD1d presents lipid antigens to invariant natural killer T (iNKT) cells. We determined a high-resolution crystal structure of human CD1d bound to α-galactosylceramide (α-GalCer) at 1.76 Å, enabling detailed investigation of ligand-sensitive conformational flexibility at Phe84, a conserved aromatic residue that caps the F′ groove. Electron density at Phe84 revealed multiple side-chain conformations, suggestive of ligand-induced plasticity. Molecular dynamics simulations indicated that the canonical rotamer is energetically favoured in the absence of a stabilising groove-occupying ligand. To assess conservation of this putative gating mechanism, we solved the first CD1d structure from a non-human primate, rhesus macaque CD1d-α-GalCer, at 1.83 Å resolution. In contrast to the human complex, Phe84 in macaque CD1d adopted a fixed conformation. As this aromatic residue is conserved across CD1 isoforms and CD1d-expressing species, and mirrors gating residues in MHC class I that regulate peptide accommodation, our findings support a shared evolutionary strategy for managing antigen diversity. These data provide critical insight into the mechanisms of antigen presentation by CD1 molecules.

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