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PDBsum entry 2uwe
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Immune system
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PDB id
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2uwe
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Contents |
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275 a.a.
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100 a.a.
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194 a.a.
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237 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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Single mhc mutation eliminates enthalpy associated with t cell receptor binding.
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Authors
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P.J.Miller,
Y.Pazy,
B.Conti,
D.Riddle,
E.Appella,
E.J.Collins.
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Ref.
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J Mol Biol, 2007,
373,
315-327.
[DOI no: ]
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PubMed id
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Abstract
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The keystone of the adaptive immune response is T cell receptor (TCR)
recognition of peptide presented by major histocompatibility complex (pMHC)
molecules. The crystal structure of AHIII TCR bound to MHC, HLA-A2, showed a
large interface with an atypical binding orientation. MHC mutations in the
interface of the proteins were tested for changes in TCR recognition. From the
range of responses observed, three representative HLA-A2 mutants, T163A, W167A,
and K66A, were selected for further study. Binding constants and co-crystal
structures of the AHIII TCR and the three mutants were determined. K66 in HLA-A2
makes contacts with both peptide and TCR, and has been identified as a critical
residue for recognition by numerous TCR. The K66A mutation resulted in the
lowest AHIII T cell response and the lowest binding affinity, which suggests
that the T cell response may correlate with affinity. Importantly, the K66A
mutation does not affect the conformation of the peptide. The change in affinity
appears to be due to a loss in hydrogen bonds in the interface as a result of a
conformational change in the TCR complementarity-determining region 3 (CDR3)
loop. Isothermal titration calorimetry confirmed the loss of hydrogen bonding by
a large loss in enthalpy. Our findings are inconsistent with the notion that the
CDR1 and CDR2 loops of the TCR are responsible for MHC restriction, while the
CDR3 loops interact solely with the peptide. Instead, we present here an MHC
mutation that does not change the conformation of the peptide, yet results in an
altered conformation of a CDR3.
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Figure 1.
Figure 1. CTL killing as a function of mutations in the
p1049/A2 Complex. Cytotoxic lysis assays (^51Cr release assays)
were performed with AHIII T cells against cells expressing
mutant A2. Data were normalized such that lytic activity against
native HLA-A2 is 100%.
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Figure 3.
Figure 3. Structure of AHIII TCR bound to p1049/A2. The AHIII
TCR α (green) and β (blue) chains, interact with the p1049/A2
surface via CDR loops. pMHC, consisting of a heavy chain, A2,
(yellow) and β[2]m (magenta), present the peptide, p1049 (red).
(Inset) The surface of the p1049/A2 is contacted by the CDR
loops of the AHIII TCR. Residues that have been mutated to
alanine for structural experiments (T163, W167, K66) are shown.
The Figure was generated using PDB coordinates 1LP9 and PyMol
[http://pymol.sourceforge.net/].
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The above figures are
reprinted
from an Open Access publication published by Elsevier:
J Mol Biol
(2007,
373,
315-327)
copyright 2007.
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