The peptide-receptive transition state of MHC class I molecules: insight from structure and molecular dynamics

• Published in: The Journal of immunology (1950) 2012-08, Vol.189 (3), p.1391-1399
• Main Authors: Mage, Michael G, Dolan, Michael A, Wang, Rui, Boyd, Lisa F, Revilleza, Maria Jamela, Robinson, Howard, Natarajan, Kannan, Myers, Nancy B, Hansen, Ted H, Margulies, David H
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; beta 2-Microglobulin - chemistry; beta 2-Microglobulin - metabolism; Crystallography, X-Ray; H-2 Antigens - chemistry; H-2 Antigens - metabolism; Histocompatibility Antigen H-2D; Humans; Ligands; Mice; Molecular Dynamics Simulation; Molecular Sequence Data; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Structure-Activity Relationship
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200831

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 3(10) 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-2L(d) 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.