MHC class I (MHC-I) proteins of the adaptive immune system require antigenic peptides for maintenance of mature conformation and immune function via specific recognition by MHC-I–restricted CD8+ T lymphocytes. New MHC-I molecules in the endoplasmic reticulum are held by chaperones in a peptide-receptive (PR) transition state pending release by tightly binding peptides. In this study, we show, by crystallographic, docking, and molecular dynamics methods, dramatic movement of a hinged unit containing a conserved 310 helix that flips from an exposed “open” position in the PR transition state to a “closed” position with buried hydrophobic side chains in the peptide-loaded mature molecule. Crystallography of hinged unit residues 46–53 of murine H-2Ld MHC-I H chain, complexed with mAb 64-3-7, demonstrates solvent exposure of these residues in the PR conformation. Docking and molecular dynamics predict how this segment moves to help form the A and B pockets crucial for the tight peptide binding needed for stability of the mature peptide-loaded conformation, chaperone dissociation, and Ag presentation.
This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, as well as by National Institutes of Health Grant AI019687 (to T.H.H.).
The sequences presented in this article have been submitted to the Protein Data Bank (http://www.rcsb.org/pdb/home/home.do) under accession numbers 3UO1, 3UYR, 3V4U, and 3V52.
The online version of this article contains supplemental material.
- Received March 14, 2012.
- Accepted May 29, 2012.