 |
PDBsum entry 1eu4
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Immune system
|
PDB id
|
|
|
|
1eu4
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Conservation and variation in superantigen structure and activity highlighted by the three-Dimensional structures of two new superantigens from streptococcus pyogenes.
|
|
|
Authors
|
|
V.L.Arcus,
T.Proft,
J.A.Sigrell,
H.M.Baker,
J.D.Fraser,
E.N.Baker.
|
|
|
Ref.
|
|
J Mol Biol, 2000,
299,
157-168.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Bacterial superantigens (SAgs) are a structurally related group of protein
toxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They are
implicated in a range of human pathologies associated with bacterial infection
whose symptoms result from SAg-mediated stimulation of a large number (2-20%) of
T-cells. At the molecular level, bacterial SAgs bind to major histocompatability
class II (MHC-II) molecules and disrupt the normal interaction between MHC-II
and T-cell receptors (TCRs). We have determined high-resolution crystal
structures of two newly identified streptococcal superantigens, SPE-H and
SMEZ-2. Both structures conform to the generic bacterial superantigen folding
pattern, comprising an OB-fold N-terminal domain and a beta-grasp C-terminal
domain. SPE-H and SMEZ-2 also display very similar zinc-binding sites on the
outer concave surfaces of their C-terminal domains. Structural comparisons with
other SAgs identify two structural sub-families. Sub-families are related by
conserved core residues and demarcated by variable binding surfaces for MHC-II
and TCR. SMEZ-2 is most closely related to the streptococcal SAg SPE-C, and
together they constitute one structural sub-family. In contrast, SPE-H appears
to be a hybrid whose N-terminal domain is most closely related to the SEB
sub-family and whose C-terminal domain is most closely related to the
SPE-C/SMEZ-2 sub-family. MHC-II binding for both SPE-H and SMEZ-2 is mediated by
the zinc ion at their C-terminal face, whereas the generic N-terminal domain
MHC-II binding site found on many SAgs appears not to be present. Structural
comparisons provide evidence for variations in TCR binding between SPE-H, SMEZ-2
and other members of the SAg family; the extreme potency of SMEZ-2 (active at
10(-15) g ml-1 levels) is likely to be related to its TCR binding properties.
The smez gene shows allelic variation that maps onto a considerable proportion
of the protein surface. This allelic variation, coupled with the varied binding
modes of SAgs to MHC-II and TCR, highlights the pressure on SAgs to avoid host
immune defences.
|
|
|
|
|
|
|
|
Figure 1.
Figure 1. Polypeptide folding and binding sites for individual superantigens. For SMEZ-2 and SPE-H, zinc-binding
residues and conserved residues on the MHC-II binding face are shown in grey. The bound zinc is shown as an
orange sphere. For TSST and SEB, residues that interact with MHC-II are shown in grey and those that interact with
the TCR are shown in yellow. TCR-binding residues are from structural data for SEB (Jardetzky et al., 1994) and
mutational studies for TSST (Hurley et al., 1995).
|
|
Figure 4.
Figure 4. Invariant residues in
superantigens. The majority of
invariant residues across the SAg
family form a hydrogen bonding or
charge-charge network cross-link-
ing a2, a4 and a5 and the intersec-
tion of the two domains. This
buried polar network is shown for
SMEZ-2 and is representative of all
the known bacterial SAg structures.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2000,
299,
157-168)
copyright 2000.
|
|
|
|
|
|
|
