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PDBsum entry 2p5e
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Immune system
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PDB id
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2p5e
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Contents |
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276 a.a.
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100 a.a.
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194 a.a.
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241 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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Crystal structures of high affinity human t-Cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry.
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Authors
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M.Sami,
P.J.Rizkallah,
S.Dunn,
P.Molloy,
R.Moysey,
A.Vuidepot,
E.Baston,
P.Todorov,
Y.Li,
F.Gao,
J.M.Boulter,
B.K.Jakobsen.
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Ref.
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Protein Eng Des Sel, 2007,
20,
397-403.
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PubMed id
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Abstract
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Naturally selected T-cell receptors (TCRs) are characterised by low binding
affinities, typically in the range 1-100 microM. Crystal structures of syngeneic
TCRs bound to peptide major histocompatibility complex (pMHC) antigens exhibit a
conserved mode of binding characterised by a distinct diagonal binding geometry,
with poor shape complementarity (SC) between receptor and ligand. Here, we
report the structures of three in vitro affinity enhanced TCRs that recognise
the pMHC tumour epitope NY-ESO(157-165) (SLLMWITQC). These crystal structures
reveal that the docking mode for the high affinity TCRs is identical to that
reported for the parental wild-type TCR, with only subtle changes in the mutated
complementarity determining regions (CDRs) that form contacts with pMHC; both
CDR2 and CDR3 mutations act synergistically to improve the overall affinity.
Comparison of free and bound TCR structures for both wild-type and a CDR3 mutant
reveal an induced fit mechanism arising from restructuring of CDR3 loops which
allows better peptide binding. Overall, an increased interface area, improved SC
and additional H-bonding interactions are observed, accounting for the increase
in affinity. Most notably, there is a marked increase in the SC for the central
methionine and tryptophan peptide motif over the native TCR.
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