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PDBsum entry 6tmo
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Immune system
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PDB id
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6tmo
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Contents |
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276 a.a.
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100 a.a.
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197 a.a.
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244 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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Molecular rules underpinning enhanced affinity binding of human t cell receptors engineered for immunotherapy.
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Authors
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R.M.Crean,
B.J.Maclachlan,
F.Madura,
T.Whalley,
P.J.Rizkallah,
C.J.Holland,
C.Mcmurran,
S.Harper,
A.Godkin,
A.K.Sewell,
C.R.Pudney,
M.W.Van der kamp,
D.K.Cole.
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Ref.
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Mol Ther Oncolytics, 2020,
18,
443-456.
[DOI no: ]
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PubMed id
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Abstract
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Immuno-oncology approaches that utilize T cell receptors (TCRs) are becoming
highly attractive because of their potential to target virtually all cellular
proteins, including cancer-specific epitopes, via the recognition of
peptide-human leukocyte antigen (pHLA) complexes presented at the cell surface.
However, because natural TCRs generally recognize cancer-derived pHLAs with very
weak affinities, efforts have been made to enhance their binding strength, in
some cases by several million-fold. In this study, we investigated the
mechanisms underpinning human TCR affinity enhancement by comparing the crystal
structures of engineered enhanced affinity TCRs with those of their wild-type
progenitors. Additionally, we performed molecular dynamics simulations to better
understand the energetic mechanisms driving the affinity enhancements. These
data demonstrate that supra-physiological binding affinities can be achieved
without altering native TCR-pHLA binding modes via relatively subtle
modifications to the interface contacts, often driven through the addition
of buried hydrophobic residues. Individual energetic components of the TCR-pHLA
interaction governing affinity enhancements were distinct and highly variable
for each TCR, often resulting from additive, or knock-on, effects beyond the
mutated residues. This comprehensive analysis of affinity-enhanced TCRs has
important implications for the future rational design of engineered TCRs as
efficacious and safe drugs for cancer treatment.
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