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PDBsum entry 2h6p
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Immune system
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PDB id
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2h6p
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References listed in PDB file
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Key reference
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Title
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Alloreactivity between disparate cognate and allogeneic pmhc-I complexes is the result of highly focused, Peptide-Dependent structural mimicry.
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Authors
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J.K.Archbold,
W.A.Macdonald,
J.J.Miles,
R.M.Brennan,
L.Kjer-Nielsen,
J.Mccluskey,
S.R.Burrows,
J.Rossjohn.
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Ref.
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J Biol Chem, 2006,
281,
34324-34332.
[DOI no: ]
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PubMed id
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Abstract
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Our understanding of the molecular mechanisms of T cell alloreactivity remains
limited by the lack of systems for which both the T cell receptor allo- and
cognate ligand are known. Here we provide evidence that a single alloreactive T
cell receptor interacts with analogous structural regions of its cognate ligand,
HLA-B*0801(FLRGRAYGL), as its allogeneic ligand, HLA-B*3501(KPIVVLHGY). The
crystal structures of the binary peptide-major histocompatibility complexes show
marked differences in the conformation of the heavy chains as well as the bound
peptides. Nevertheless, both epitopes possess a prominent solvent-exposed
aromatic residue at position 7 flanked by a small glycine at position 8 of the
peptide determinant. Moreover, regions of close structural homology between the
heavy chains of HLA B8 and HLA B35 coincided with regions that have previously
been implicated in "hot spots" of T cell receptor recognition. The
avidity of this human T cell receptor was also comparable for the allo- and
cognate ligand, consistent with the modes of T cell receptor binding being
broadly similar for these complexes. Collectively, it appears that highly
focused structural mimicry against a diverse structural background provides a
basis for the observed alloreactivity in this system. This cross-reactivity
underpins the T cell degeneracy inherent in the limited mature T cell repertoire
that must respond to a vast diversity of microbial antigens.
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Figure 4.
FIGURE 4. Structure of the allogeneic stimulating peptide,
KPI, complexed to the MHC. The cytochrome P450 derived peptide,
KPIVVLHGY (aqua), sitting in the peptide binding cleft of the
MHC, HLA-B^*3501 (green). The surrounding final 2F[o] - F[c]
electron density for the peptide is shown in mesh format. This
figure shows the positions of key anchor residues (Pro^2 and
Tyr^9) and possible TCR contact residues (Val^4, Val^5, and
His^7).
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Figure 6.
FIGURE 6. Highly focused molecular mimicry between the
allo- and cognate ligands explains JL9 cross-reactivity. Surface
representation of (self-HLA-B^*0801^FLR (A) and
allo-HLA-B^*3501^KPI (B). The surface of HLA-B^*0801^FLR and
HLA-B^*3501^KPI differ, especially around the peptides and their
binding clefts. The polymorphic residues are colored in orange,
the FLRGRAYGL peptide is colored in pink, and the KPIVVLHGY
peptide is colored in aqua. For the polymorphic residues, the
HLA-B^*0801 residue is listed first followed by the residue
number and then the corresponding HLA-B^*3501 residue. The
energetic hot spot residues for recognition of HLA-B^*0801^FLR
by the LC13 TCR are also shown (yellow). C, overlay of the  1 and
2
helices of HLA-B^*0801 (blue) and HLA-B^*3501 (green). The FLR
peptide is colored in pink, and the KPI peptide is colored in
aqua. The CDR loops of the LC13 TCR are shown in orange. The MHC
residue positions known to be important for LC13 recognition of
HLA-B^*0801^FLR are highlighted in yellow. In particular, the
three residues of the restriction triad at positions 65, 69, and
155 appear to be conserved structurally.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
34324-34332)
copyright 2006.
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