Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule

The structural basis of the interaction between the CD4 coreceptor and a cl ass II major histocompatibility complex (MHC) is described. The crystal str ucture 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 (pMHCI I) shows that only the "top corner" of the CD4 molecule directly contacts p MHCII. The CD4 Phe-43 side chain extends into a hydrophobic concavity forme d by MHC residues from both alpha2 and beta2 domains. A ternary model of th e CD4-pMHCII-T-cell receptor (TCR) reveals that the complex appears V-shape d with the membrane-proximal pMHCII at the apex. This configuration exclude s a direct TCR-CD4 interaction and suggests how TCR and CD4 signaling is co ordinated around the antigenic pMHCII complex. Human CD4 binds to HIV gp120 in a manner strikingly similar to the way in which CD4 interacts with pMHC II. 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.