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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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PDB id:
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| Name: |
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Immune system
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Title:
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Structure determination of an enhanced affinity tcr, a24b17, in complex with hla-a 02:01 Presenting a mart-1 peptide, eaagigiltv
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Structure:
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Mhc class i antigen. Chain: a. Engineered: yes. Beta-2-microglobulin. Chain: b. Engineered: yes. Eaagigiltv. Chain: c. Engineered: yes.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-a. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: b2m, cdabp0092, hdcma22p. Synthetic: yes. Expression_system_taxid: 562
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Resolution:
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2.10Å
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R-factor:
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0.174
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R-free:
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0.209
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Authors:
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P.J.Rizkallah,D.K.Cole
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Key ref:
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R.M.Crean
et al.
(2020).
Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy.
Mol Ther Oncolytics,
18,
443-456.
PubMed id:
DOI:
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Date:
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05-Dec-19
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Release date:
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07-Oct-20
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PROCHECK
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Headers
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References
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A0A5B8RNS7
(A0A5B8RNS7_HUMAN) -
MHC class I antigen (Fragment) from Homo sapiens
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Seq:
Struc:
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337 a.a.
276 a.a.
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P61769
(B2MG_HUMAN) -
Beta-2-microglobulin from Homo sapiens
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Seq:
Struc:
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119 a.a.
100 a.a.*
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DOI no:
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Mol Ther Oncolytics
18:443-456
(2020)
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PubMed id:
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Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy.
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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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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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