This animated 3D structure was determined by X-ray analysis of crytallized complexes created from the recombinant extracellular domain of a truncated HLA-B MHC class I alpha subunit in noncovalent association with beta₂-microglobin, a smaller, conserved MHC I subunit. The αβ dimer is also associated noncovalently with an antigenic peptide derived from the Epstein Barr virus latent membrane protein 2 (LMP2). This peptide/MHC class I complex could potentially be recognized by T-cell receptors (TCRs) expressed on a small subset of cytotoxic T-lymphocyte (CTL) clones in individuals expressing the HLA-B*1402 alpha subunit variant.

This 3D structure was determined by X-ray crystal analysis of the recombinant extracellular domain of a truncated HLA-B class I alpha subunit noncovelantly associated with the smaller and MHC I-conserved beta-2-microglobulin subunit, thereby forming an MHC I αβ₂m heteodimer. The "peptide binding pocket" of this dimer is formed by the α-subunit and is occupied here by an antigenic peptide derived from the Epstein Barr virus (EBV) latent membrane protein 2 (LMP2). Such peptide/MHC I complexes are potentially recognized by the T-cell receptors (TCRs) expressed on T-cytotoxic (T_C) lymphocyes or CTLs as discussed below.

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 criss-crossing anti-parallel β-strands originating from just the α-subunit. The "sides" of the pocket are formed from two α-helices - again originating from the α-subunit.
• The atoms in the LMP2 peptide in the peptide-binding pocket are spaceifilled with the atom coloration highlighted according to the Corey–Pauling–Koltun (CPK) atomic color scheme.
• Note that peptide binding in the MHC I pocket is very much weaker than and less specific than other receptor/ligand (or enzyme/substrate) interactions normally found in biological systems. Thus, with broader binding specificity, any MHC I molecule can bind and "present" many different peptides with semi-homologous AA sequences that range from 8-12 AA residues.
• MHC I molecules are expressed on virtually every cell of the body. Ribosomally synthesized MHC I α and β₂m polypeptides are threaded into the endoplasimic reticulum (RER) where they encounter a "sea of peptides" produced by proteosomes that proteolytically fragment "aged" proteins in cell as well as foreign proteins from internal or internalized pathogens if present in the same cell.
• MHC I//peptide complexes that form in the ER are routed to the APC surface for "presentation" to the unique T-cell receptors (TCRs) expressed on of circulating CTL clones.
• However, self peptides "presented" by these MHC I complexes rarely activate circulating CTL 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.
• Thus, CTL functions are typically activated only if the homogenous (clonotypic) TCRs on CTL clones detect MHC I complexes with foreign peptides.
• Because these interactions are collectively weak, CTL activation and target cell killing are usually enhanced when multiple α-subunit/peptide complexes on the target cell surface bind to multiple TCRs and multiple (CD8α)₂ co-receptors (which are not included in this structure) bind to the CD8 docking regions of the corresponding α-subunits.

Additional immunological and immunogenetics considerations from this structure:

• Note that the HLA geneotype of any any individual includes 6 co-dominantly expressed diploid genes for MHC I α-subunits. Because there are many hundreds of alleles for these genes in the human population, the combination of MHC I alleles produced by any one individual is likely to be different from the combinations found in other individuals unless they are genetcally related.
• Nevertheless, the peptide antigen-presenting diversity of MHC class I molecules in any individual is exponentially increased by the diversity of MHC I alleles, which obviously increases the likelihood that some circulating CTL clones could be activated by some of the MHC I/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 structural image.

Flash animation illustrating peptide processing and MHC I presentation.