Crystal Structure of the Human CD4 N-Terminal Two-Domain Fragment Complexed to a Class II MHC Molecule

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-09, Vol.98 (19), p.10799-10804
• Main Authors: Wang, Jia-huai, Meijers, Rob, Xiong, Yi, Liu, Jin-huan, Sakihama, Toshiko, Zhang, Rongguang, Joachimiak, Andrzej, Reinherz, Ellis L.
• Format: Article
• Language: English
• Subjects: AFFINITY; Amino Acid Sequence; Animals; Biological Sciences; CD4 antigen; CD4 Antigens - chemistry; CD4 Antigens - genetics; CD4 Antigens - immunology; Cell membranes; CHAINS; CONFIGURATION; CRYSTAL STRUCTURE; Crystallography, X-Ray; Crystals; GLYCOPROTEINS; histocompatibility antigen H-2; Histocompatibility Antigens Class II - chemistry; Histocompatibility Antigens Class II - immunology; HISTOCOMPATIBILITY COMPLEX; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - immunology; HIV-1; Humans; Immunology; Ligands; MATERIALS SCIENCE; Mice; Models, Molecular; Molecular interactions; Molecular Sequence Data; Molecular structure; Molecules; Mutagenesis; PEPTIDES; Protein Structure, Tertiary; Receptors, Antigen, T-Cell - chemistry; RESIDUES; T cell antigen receptors; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.191124098

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-Akclass 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 α2 and β2 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.