2P5E: Crystal Structures Of High Affinity Human T-Cell Receptors Bound To Pmhc Reveal Native Diagonal Binding Geometry

Citation:
Abstract
Naturally selected T-cell receptors (TCRs) are characterised by low binding affinities, typically in the range 1-100 microM. Crystal structures of syngeneic TCRs bound to peptide major histocompatibility complex (pMHC) antigens exhibit a conserved mode of binding characterised by a distinct diagonal binding geometry, with poor shape complementarity (SC) between receptor and ligand. Here, we report the structures of three in vitro affinity enhanced TCRs that recognise the pMHC tumour epitope NY-ESO(157-165) (SLLMWITQC). These crystal structures reveal that the docking mode for the high affinity TCRs is identical to that reported for the parental wild-type TCR, with only subtle changes in the mutated complementarity determining regions (CDRs) that form contacts with pMHC; both CDR2 and CDR3 mutations act synergistically to improve the overall affinity. Comparison of free and bound TCR structures for both wild-type and a CDR3 mutant reveal an induced fit mechanism arising from restructuring of CDR3 loops which allows better peptide binding. Overall, an increased interface area, improved SC and additional H-bonding interactions are observed, accounting for the increase in affinity. Most notably, there is a marked increase in the SC for the central methionine and tryptophan peptide motif over the native TCR.
PDB ID: 2P5EDownload
MMDB ID: 59237
PDB Deposition Date: 2007/3/15
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 1.89  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 2P5E: pentameric; determined by author and by software (PISA,PQS)
Molecular Components in 2P5E
Label Count Molecule
Proteins (5 molecules)
1
HLA Class I Histocompatibility Antigen, A-2 Alpha Chain(Gene symbol: HLA-A)
Molecule annotation
1
Beta-2-microglobulin(Gene symbol: B2M)
Molecule annotation
1
Cancertestis Antigen 1B(Gene symbol: CTAG1B)
Molecule annotation
1
T-cell Receptor, Alpha Chain
Molecule annotation
1
Hypothetical Protein
Molecule annotation
Chemicals (16 molecules)
1
8
2
1
3
5
4
1
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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