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PDBsum entry 3d39
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Immune system
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PDB id
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3d39
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Contents |
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275 a.a.
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100 a.a.
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200 a.a.
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245 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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Fluorine substitutions in an antigenic peptide selectively modulate t-Cell receptor binding in a minimally perturbing manner.
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Authors
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K.H.Piepenbrink,
O.Y.Borbulevych,
R.F.Sommese,
J.Clemens,
K.M.Armstrong,
C.Desmond,
P.Do,
B.M.Baker.
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Ref.
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Biochem J, 2009,
423,
353-361.
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PubMed id
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Abstract
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TCR (T-cell receptor) recognition of antigenic peptides bound and presented by
MHC (major histocompatibility complex) molecules forms the basis of the cellular
immune response to pathogens and cancer. TCRs bind peptide-MHC complexes weakly
and with fast kinetics, features which have hindered detailed biophysical
studies of these interactions. Modified peptides resulting in enhanced TCR
binding could help overcome these challenges. Furthermore, there is considerable
interest in using modified peptides with enhanced TCR binding as the basis for
clinical vaccines. In the present study, we examined how fluorine substitutions
in an antigenic peptide can selectively impact TCR recognition. Using a
structure-guided design approach, we found that fluorination of the Tax peptide
[HTLV (human T-cell lymphotropic virus)-1 Tax(11-19)] enhanced binding by the
Tax-specific TCR A6, yet weakened binding by the Tax-specific TCR B7. The
changes in affinity were consistent with crystallographic structures and
fluorine chemistry, and with the A6 TCR independent of other substitutions in
the interface. Peptide fluorination thus provides a means to selectively
modulate TCR binding affinity without significantly perturbing peptide
composition or structure. Lastly, we probed the mechanism of fluorine's effect
on TCR binding and we conclude that our results were most consistent with a
'polar hydrophobicity' mechanism, rather than a purely hydrophobic- or
electrostatic-based mechanism. This finding should have an impact on other
attempts to alter molecular recognition with fluorine.
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