title: A structural and molecular dynamics approach to understanding the peptide-receptive transition state of MHC-I molecules.
abstract: The mature conformation of major histocompatibility complex class I (MHC-I) proteins depends on the presence of bound peptides, permitting recognition at the cell surface by CD8(+) T lymphocytes. Newly synthesized MHC-I molecules in the endoplasmic reticulum are maintained in a peptide-receptive (PR) transition state by several chaperones until they are released concomitant with the loading of peptides. By determining the crystallographic structure of a region of an MHC-I molecule that is recognized by a unique monoclonal antibody and comparing this with docking and molecular dynamics simulations with the whole molecule, we demonstrate the movement of a hinged unit supporting the part of the binding groove that interacts with the amino terminal residues of the bound peptide. This unit contains a conserved 310 helix that flips from an exposed "open" position in the PR form to a "closed" position in the peptide-loaded (PL) mature molecule. These analyses indicate how this segment of the MHC-I molecule moves to help establish the A and B pockets critical for tight peptide binding and the stable structure required for antigen presentation and T cell recognition at the cell surface.
authors.affiliation: Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases NIAID, NIH, Bethesda, MD 20892-1892, USA. mmage@mail.nih.gov
authors.forename: Michael G
authors.initials: MG
authors.lastname: Mage
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dolan
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Boyd
authors.forename: Maria Jamela
authors.initials: MJ
authors.lastname: Revilleza
authors.forename: Howard
authors.initials: H
authors.lastname: Robinson
authors.forename: Kannan
authors.initials: K
authors.lastname: Natarajan
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Myers
authors.forename: Ted H
authors.initials: TH
authors.lastname: Hansen
authors.forename: David H
authors.initials: DH
authors.lastname: Margulies
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018360:Crystallography, X-Ray; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051192:Receptors, Pattern Recognition / Q000276:immunology* / Q000648:ultrastructure*
chemical_list: D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D051192:Receptors, Pattern Recognition