Enterotoxin B Superantigen Complex with MHC Class II
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An exposed surface located on top of each SEB molecule in this image has been implicated (by mutational analysis) in T-cell receptor binding. The T-cell receptor binding sites on the superantigen molecules in the complex are also positioned near but not within the MHC peptide binding pockets. Thus, a mechanism for antigen-nonspecific, T-cell receptor crosslinking by superantigen is suggested by the fact that two SEB molecules are vertically oriented in similar directions in this complex
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1. HLA-DR1 (ab)2 class II multi-peptide complex with two (Ala)13  antigenic peptides and two SEB molecules.
2. SEB binds near to the antigenic peptide but still outside the peptide-binding pocket of HLA-DR1.
3. Complementary hydrophobic: hydrophobic and polar:polar interactions defining the binding specificity of the SEB:a-subunit complex. Note how the positively charged amino group of Lys39-NH3+ of the a-subunit is positioned so as to form hydrogen bonds or salt bridges with 4 oxygen atoms of the SEB molecule, including the 2 g-carboxylate oxygen atoms of Glu67-COO- (each with 1/2 negative charge) and the phenolic oxygen atoms of Tyr89-OH and Tyr115-OH.
4. Amino acid sidechain residues of SEB (in gray) implicated in binding to T cell receptor Vb chains.
Color coding: ab (HLA-DR1);a1 and a2 = a subunit domains; b1 and b2 = b subunit domains; (Ala)13 = synthetic polyalanine peptide; enterotoxin B (SEB); polar and hydrophobic regions; and amino acid sidechain residues of SEB implicated in Vb chain T cell receptor binding.
Staphylococcal enterotoxin B (SEB) is a superantigen that binds the membrane-distal, a1-domain of the a subunit of the human HLA-DR1 class II MHC molecule. Buttons 1 and 2 below animate this interaction showing that SEB binds near to but still outside the MHC peptide-binding pocket. In particular, SEB binds to a segment of the b-strands and one a-helix that partially shape the exterior of the peptide-binding pocket. Button 3 animates the complementary hydrophobic and polar surfaces of the SEB molecule and the a1-domain that define the specificity of their interaction.
Although it is not shown here, SEB also binds to some but not all isoforms of the human T cell receptor Vb chain, including Vb3, Vb12, Vb14, Vb15, Vb17, and Vb20. Button 4 highlights several SEB amino acid sidechains (imaged in white) that are implicated (by point-mutational analysis) in the binding reactions with T cell receptor Vb chains. SEB binds Vb chains near to but still outside their antigen-binding sites. Specifically, SEB binds to a region of the Vb chain which is structurally more conserved than the hypervariable regions that shape part of the antigen-binding site.
These data help explain how superantigen bypasses the normal routes for specific recognition of antigen by MHC class II molecules and T cell receptors resulting in antigen-nonspecific activation of the cells expressing these receptors. The consequence is an unusually vigorous polyclonal activation of T cells with an exaggerated immune-like response that can be life-threatening in the worst-case scenarios.
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© Sean R. Christensen and Duane W. Sears
May 25, 2015