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PDBsum entry 2f53
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Immune system
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PDB id
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2f53
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Contents |
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275 a.a.
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100 a.a.
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193 a.a.
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243 a.a.
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References listed in PDB file
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Key reference
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Title
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Directed evolution of human t cell receptor cdr2 residues by phage display dramatically enhances affinity for cognate peptide-Mhc without increasing apparent cross-Reactivity.
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Authors
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S.M.Dunn,
P.J.Rizkallah,
E.Baston,
T.Mahon,
B.Cameron,
R.Moysey,
F.Gao,
M.Sami,
J.Boulter,
Y.Li,
B.K.Jakobsen.
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Ref.
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Protein Sci, 2006,
15,
710-721.
[DOI no: ]
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PubMed id
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Abstract
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The mammalian alpha/beta T cell receptor (TCR) repertoire plays a pivotal role
in adaptive immunity by recognizing short, processed, peptide antigens bound in
the context of a highly diverse family of cell-surface major histocompatibility
complexes (pMHCs). Despite the extensive TCR-MHC interaction surface,
peptide-independent cross-reactivity of native TCRs is generally avoided through
cell-mediated selection of molecules with low inherent affinity for MHC. Here we
show that, contrary to expectations, the germ line-encoded complementarity
determining regions (CDRs) of human TCRs, namely the CDR2s, which appear to
contact only the MHC surface and not the bound peptide, can be engineered to
yield soluble low nanomolar affinity ligands that retain a surprisingly high
degree of specificity for the cognate pMHC target. Structural investigation of
one such CDR2 mutant implicates shape complementarity of the mutant CDR2 contact
interfaces as being a key determinant of the increased affinity. Our results
suggest that manipulation of germ line CDR2 loops may provide a useful route to
the production of high-affinity TCRs with therapeutic and diagnostic potential.
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Figure 3.
Structural depiction of the CDR2 mutant interactions in the
c49c50 --pMHC complex. (A) The CDR2[beta] loop mutations (GAGI
to SVGM). The 2BNR model is depicted in red; the c49c50 TCR is
colored by atom type, mostly green; the c49c50 MHC is mostly
red. Dotted lines indicate contacts between mutated side chains
and MHC residues. (B) The CDR2[alpha] loop mutations (QSS to
PFW): Q155 of the MHC is pushed deeper into the pocket by the
close approach of F51, while W52 forces a tighter packing of the
CDR1[alpha] Y30 against W5 of the peptide. The 2BNR MHC is red
and the c49c50 TCRa is mostly orange. The figures were prepared
using PyMOL (DeLano 2002).
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Figure 4.
Electron density contoured at 2[sigma] around the identified
metal site (black) in the peptide binding groove of the MHC.
Some of the approach contacts are indicated. MHC residues are
blue. The bound peptide is yellow. TCR [alpha] and [beta] chain
residues are orange and green, respectively. Water molecules are
displayed as purple spheres. The figure was generated using
PyMOL (DeLano 2002).
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(2006,
15,
710-721)
copyright 2006.
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