title: Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule.
abstract: The structural basis of the interaction between the CD4 coreceptor and a class II major histocompatibility complex (MHC) is described. The crystal structure of a complex containing the human CD4 N-terminal two-domain fragment and the murine I-A(k) class II MHC molecule with associated peptide (pMHCII) shows that only the "top corner" of the CD4 molecule directly contacts pMHCII. The CD4 Phe-43 side chain extends into a hydrophobic concavity formed by MHC residues from both alpha 2 and beta 2 domains. A ternary model of the CD4-pMHCII-T-cell receptor (TCR) reveals that the complex appears V-shaped with the membrane-proximal pMHCII at the apex. This configuration excludes a direct TCR-CD4 interaction and suggests how TCR and CD4 signaling is coordinated around the antigenic pMHCII complex. Human CD4 binds to HIV gp120 in a manner strikingly similar to the way in which CD4 interacts with pMHCII. Additional contacts between gp120 and CD4 give the CD4-gp120 complex a greater affinity. Thus, ligation of the viral envelope glycoprotein to CD4 occludes the pMHCII-binding site on CD4, contributing to immunodeficiency.
authors.affiliation: Laboratory of Immunobiology and Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. jwang@dfci.harvard.edu
authors.forename: J H
authors.initials: JH
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Meijers
authors.forename: Y
authors.initials: Y
authors.lastname: Xiong
authors.forename: J H
authors.initials: JH
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Sakihama
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Joachimiak
authors.forename: E L
authors.initials: EL
authors.lastname: Reinherz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology; D015497:HIV-1; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D000949:Histocompatibility Antigens Class II; C111388:I-Ak antigen; D011948:Receptors, Antigen, T-Cell