Crystal structures of MHC class I complexes reveal the elusive intermediate conformations explored during peptide editing

Studies have suggested that MHC class I (MHC I) molecules fluctuate rapidly between numerous conformational states and these motions support peptide sampling. To date, MHC I intermediates are largely uncharacterized experimentally and remain elusive. Here, we present x-ray crystal structures of HLA-B8 loaded with 20mer peptides that show pronounced distortions at the N-terminus of the groove. Long stretches of N-terminal amino acid residues are missing in the electron density maps creating an open-ended groove. Our structures also reveal highly unusual features in MHC I-peptide interaction at the N-terminus of the groove. Molecular dynamics simulations indicate that the complexes have varying degrees of conformational flexibility in a manner consistent with the structures. We suggest that our structures have captured the remarkable molecular dynamics of MHC I-peptide interaction. The visualization of peptide-dependent conformational motions in MHC I is a major step forward in our conceptual understanding of dynamics in high-affinity peptide selection. The unusual crystal structures of MHC I-peptide complexes provide a visualization of the remarkable ability of the groove to adapt conformationally to bound peptides, explaining how MHC I molecules edit peptides in antigen presentation.

Automated summary

This study presents X-ray crystal structures of MHC I molecules interacting with peptides, revealing conformational fluctuations and providing a better understanding of peptide selection dynamics. The unusual crystal structures of the MHC I-peptide complexes explain how MHC I molecules edit peptides in antigen presentation.