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

By Jia-huai Wang, R. Meijers, Y. Xiong, Jin‐huan Liu, T. Sakihama, Rong-guang Zhang, A. Joachimiak, Ellis L. Reinherz. 2001

260 citations recorded by the source corpus.

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-Ak 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 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.

Subfields: Immunology, Virology

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Citations in the corpus

• Towards automated crystallographic structure refinement with phenix.refine (2012, neutral): “Low-resolution structures The structures with PDB entries 1jl4 (Wang et al., 2001), 2gsz (Satyshur et al., 2007), 1yi5 (Bourne et al., 2005), 2wjx (Clayton et al., 2009), 3eob (Li et al., 2009), 1av1 (Brouillette & Anantharamaiah, 1995), 3bbw (Qiu et al., 2008) and 2i07 (Janssen et al., 2006) were…”
• Direct observation of ligand recognition by T cells (2002, background): “In particular, it has been shown that CD4 binds the MHC at almost a 90° degree angl”
• Decade-Long Safety and Function of Retroviral-Modified Chimeric Antigen Receptor T-cells (2012, background): “Alternatively, binding of the extracellular CD4 portion of the CD4ζ chimera with its low affinity ligand, MHC class II, might lead to signaling through the ζ chain to promote persistence (36).”
• The Crystal Structure of a TL/CD8αα Complex at 2.1 Å Resolution: Implications for Modulation of T Cell Activation and Memory (2003, unknown): “A Leu29Ala domains (Wang et al., 2001).”
• LAG3 (CD223) as a Cancer Immunotherapy Target (2017, background): “LAG3 and CD4 also exhibit rigidity between the D1 and D2 domains and between the D3 and D4 domains due to a long, continuous β-strand that extends between these domains, but with relative flexibility between the D1–D2 and D3–D4 substructures (15, 16).”
• The changing faces of glutathione, a cellular protagonist. (2003, background): “The region of human CD4 that interacts with MHC class II lies mainly within the C′′ and D strands of domain 1 (D1), the N-terminal IgV domain (Wang et al., 2001).”