This 3D structure was determined by X-ray crystal analysis of the recombinant extracellular domains of truncated HLA-DR1 class II alpha and beta subunits that are noncovelantly associated as αβ heteodimers and form a "peptide binding pocket," which is occupied here by an influenza virus antigenic peptide.

The heterodimers are also noncovalently associated with the recombinant extracellular domains of truncated CD4, a co-receptor for MHC class II molecules normally expressed on the membranes of T-helper (T_H) lymphoctyes. As shown here, the membrane-distal domain of CD4 (derived from T_H cells) binds to the membrane-proximal CD4 docking site (AA residues 134-148) of the MHC II β-subunit that is coodinately co-expressed with the α-subunit on the membranes of so-called "antigen-presenting" cells (APCs), including antibody-producing B-cells, macrophoges (Mφs), and dendritic cells (DCs).

The complete structure here is actually a noncolvalently associated, dimerized (αβ-peptide-CD4)₂ complex. This finding is consistent with studies indicating that cell surface MHC class II αβ dimers tend to self-aggegrate into larger complexes on the membranes of APCs.

Additional notes about the structures in this complex:

• The truncated subunits lack both the transmembrane and C-terminal intracellular/cytoplasmic domains of the full-length subunits.
• The 3D polypeptide backbone structures of the subunits fold into mixed segments of β-pleated sheets - as depicted here by parallel ribbons - and α-helices - as depicted by spiral ribbons. Disulfide (S-S) bonds between cysteine sidechains also partially stabilizied the 3D structure.
• Note that the "floor" of the peptide-binding pocket is formed by cross-crossing anti-parallel β-strands originating from both subunits. The "sides" of the pocket are formed from two α-helices - one from each subunit.
• The flu peptide in the peptide-binding pocket is spaceifilled with atom colors highlighted according to the Corey–Pauling–Koltun (CPK) atomic color scheme.
• Note that peptide binding in the MHC II pocket is very much weaker than and less specific than other receptor/ligand (or enzyme/substrate) interactions. Thus, the pocket of any MHC II molecule can bind and "present" many different peptides with semi-homologous AA sequences ranging from 13-18 AA residues.
• After intracellular polypeptide synthesis, MHC II molecules are routed to the intracellular endosomes and phagosomes of APCs where they encounter a "sea of peptides" resulting from the proteolytic breakdown of "aged" proteins and possibly foreign proteins from internalized pathogens.
• MHC II//peptide complexes that form in these intracellular compartments are routed to the APC surface for "presentation" to the unique T-cell receptors (TCRs) expressed on different clones of circulating T-helper (T_H) cells.
• However, self peptides "presented" by these MHC II complexes rarely activate circulating T_H cells because several toleragenic mechansims arise during T-cell develoment that either eliminate or silence self-reactive T cells, the primary exception being when autoimmuniity arises in some individuals.
• Typically, T_H cells, which mainly function by releasing cytokines that control the activities of other immune cells, are thenselves activated after homogenous (clonotypic) TCRs on a given T_H clone bind multiple MHC II complexes with foreign antigenic peptides as presented on any given APC.
• Because these interactions are collectively weak, optimal T_H cell activation is usually enhanced by the binding of multiple CD4 co-receptors on the individual T_H cells to multiple β-subunits on any APC.

Additional immunological and immunogenetics considerations from this structure:

• Note that the HLA geneotype of any any individual can potentially produce about 44 unique MHC II molecules (max) based on the combined diploid number of MHC II α-subunit and β-subunit genes. Because there are many hundreds of alleles for these genes in the human population, the MHC II αβ allelic combinations produced by any one individual are likely to be different from the combinations found in other individuals unless they are genetcally related.
• Nevertheless, the peptide antigen-presenting diversity of MHC II molecules in any individual is exponentially increased by the fact that multiple peptides can bind to the individual MHC II pockets, which obviously increases the likelihood that some circulating T_H cell clones could be activated by some of the MHC II/antigen complexes.
• Such diversity is thought to have evolved as an essential immunological mechanism to help protect individuals from the wide spectrum of pathogens in the environment and also protect the human species as a whole from devistation by particularly deadly pathogens.

For additional insights, click on the the buttons and checkboxes on the opposite webpage to explore this structure. Also, click on the mouse icon below to find instructions for manipulaing the structure with the mouse or for issuing JSMol commands from popup menus opened by right-clicking anywhere on the structure itself.

Flash animation illustrating peptide processing and MHC II presentation.