title: The peptide-receptive transition state of MHC class I molecules: insight from structure and molecular dynamics.
abstract: 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.
authors: Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mmage@mail.nih.gov
authors: Michael G
authors: MG
authors: Mage
authors: Michael A
authors: MA
authors: Dolan
authors: Rui
authors: R
authors: Wang
authors: Lisa F
authors: LF
authors: Boyd
authors: Maria Jamela
authors: MJ
authors: Revilleza
authors: Howard
authors: H
authors: Robinson
authors: Kannan
authors: K
authors: Natarajan
authors: Nancy B
authors: NB
authors: Myers
authors: Ted H
authors: TH
authors: Hansen
authors: David H
authors: DH
authors: Margulies
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D006183:H-2 Antigens / Q000737:chemistry / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D008024:Ligands; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000378:metabolism
chemical_list: D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D008024:Ligands; D010446:Peptide Fragments; D001613:beta 2-Microglobulin