Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule
Reinherz, Ellis L.
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CitationWang, J.-h., R. Meijers, Y. Xiong, J.-h. Liu, T. Sakihama, R. Zhang, A. Joachimiak, and E. L. Reinherz. 2001. “Crystal Structure of the Human CD4 N-Terminal Two-Domain Fragment Complexed to a Class II MHC Molecule.” Proceedings of the National Academy of Sciences 98 (19). Proceedings of the National Academy of Sciences: 10799–804. doi:10.1073/pnas.191124098.
AbstractThe 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 alpha2 and beta2 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.
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