2p5e: Difference between revisions
New page: left|200px<br /> <applet load="2p5e" size="450" color="white" frame="true" align="right" spinBox="true" caption="2p5e, resolution 1.89Å" /> '''Crystal Structures ... |
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caption="2p5e, resolution 1.89Å" /> | caption="2p5e, resolution 1.89Å" /> | ||
'''Crystal Structures of High Affinity Human T-Cell Receptors Bound to pMHC Reveal Native Diagonal Binding Geometry'''<br /> | '''Crystal Structures of High Affinity Human T-Cell Receptors Bound to pMHC Reveal Native Diagonal Binding Geometry'''<br /> | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
==About this Structure== | ==About this Structure== | ||
2P5E is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, SO4, EPE, GOL and IPA as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 2P5E is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=EPE:'>EPE</scene>, <scene name='pdbligand=GOL:'>GOL</scene> and <scene name='pdbligand=IPA:'>IPA</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P5E OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: t-cell receptor]] | [[Category: t-cell receptor]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:27:02 2008'' | ||
Revision as of 14:27, 23 January 2008
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Crystal Structures of High Affinity Human T-Cell Receptors Bound to pMHC Reveal Native Diagonal Binding Geometry
OverviewOverview
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.
About this StructureAbout this Structure
2P5E is a Protein complex structure of sequences from Homo sapiens with , , , and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structures of high affinity human T-cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry., Sami M, Rizkallah PJ, Dunn S, Molloy P, Moysey R, Vuidepot A, Baston E, Todorov P, Li Y, Gao F, Boulter JM, Jakobsen BK, Protein Eng Des Sel. 2007 Aug;20(8):397-403. Epub 2007 Jul 20. PMID:17644531
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