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. |
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HLA-DR1 (ab)2 class II multi-peptide complex with two (Ala)13 antigenic peptides and two SEB
molecules. |
| 2. |
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SEB binds near to the antigenic peptide but still outside the peptide-binding
pocket of HLA-DR1. |
| 3. |
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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. |
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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. |
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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.
