2f54
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Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity
OverviewOverview
The mammalian alpha/beta T cell receptor (TCR) repertoire plays a pivotal, role in adaptive immunity by recognizing short, processed, peptide, antigens bound in the context of a highly diverse family of cell-surface, major histocompatibility complexes (pMHCs). Despite the extensive TCR-MHC, interaction surface, peptide-independent cross-reactivity of native TCRs, is generally avoided through cell-mediated selection of molecules with low, inherent affinity for MHC. Here we show that, contrary to expectations, the germ line-encoded complementarity determining regions (CDRs) of human, TCRs, namely the CDR2s, which appear to contact only the MHC surface and, not the bound peptide, can be engineered to yield soluble low nanomolar, affinity ligands that retain a surprisingly high degree of specificity for, the cognate pMHC target. Structural investigation of one such CDR2 mutant, implicates shape complementarity of the mutant CDR2 contact interfaces as, being a key determinant of the increased affinity. Our results suggest, that manipulation of germ line CDR2 loops may provide a useful route to, the production of high-affinity TCRs with therapeutic and diagnostic, potential.
DiseaseDisease
Known diseases associated with this structure: Abacavir hypersensitivity, susceptibility to OMIM:[142800], Ankylosing spondylitis, susceptibility to, 1 OMIM:[142800], Hypoproteinemia, hypercatabolic OMIM:[109700], Stevens-Johnson syndrome, susceptibility to OMIM:[142800]
About this StructureAbout this Structure
2F54 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity., Dunn SM, Rizkallah PJ, Baston E, Mahon T, Cameron B, Moysey R, Gao F, Sami M, Boulter J, Li Y, Jakobsen BK, Protein Sci. 2006 Apr;15(4):710-21. PMID:16600963
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