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PDBsum entry 5e9d
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Protein binding
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PDB id
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5e9d
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Contents |
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266 a.a.
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98 a.a.
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110 a.a.
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115 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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An engineered switch in t cell receptor specificity leads to an unusual but functional binding geometry.
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Authors
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D.T.Harris,
N.K.Singh,
Q.Cai,
S.N.Smith,
C.W.Vander kooi,
E.Procko,
D.M.Kranz,
B.M.Baker.
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Ref.
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Structure, 2016,
24,
1142-1154.
[DOI no: ]
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PubMed id
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Abstract
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Utilizing a diverse binding site, T cell receptors (TCRs) specifically
recognize a composite ligand comprised of a foreign peptide and a major
histocompatibility complex protein (MHC). To help understand the determinants of
TCR specificity, we studied a parental and engineered receptor whose peptide
specificity had been switched via molecular evolution. Altered specificity was
associated with a significant change in TCR-binding geometry, but this did not
impact the ability of the TCR to signal in an antigen-specific manner. The
determinants of binding and specificity were distributed among contact and
non-contact residues in germline and hypervariable loops, and included
disruption of key TCR-MHC interactions that bias αβ TCRs toward particular
binding modes. Sequence-fitness landscapes identified additional mutations that
further enhanced specificity. Our results demonstrate that TCR specificity
arises from the distributed action of numerous sites throughout the interface,
with significant implications for engineering therapeutic TCRs with novel and
functional recognition properties.
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