2pyf

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[[Image:2pyf.jpg|left|200px]]
 
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{{Structure
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==Crystal Structures of High Affinity Human T-Cell Receptors Bound to pMHC RevealNative Diagonal Binding Geometry Unbound TCR Clone 5-1==
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|PDB= 2pyf |SIZE=350|CAPTION= <scene name='initialview01'>2pyf</scene>, resolution 2.20&Aring;
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<StructureSection load='2pyf' size='340' side='right'caption='[[2pyf]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
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<table><tr><td colspan='2'>[[2pyf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PYF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PYF FirstGlance]. <br>
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|ACTIVITY=
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
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|GENE=
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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|DOMAIN=
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2pyf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pyf OCA], [https://pdbe.org/2pyf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2pyf RCSB], [https://www.ebi.ac.uk/pdbsum/2pyf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2pyf ProSAT]</span></td></tr>
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|RELATEDENTRY=[[2f53|2F53]], [[2f54|2F54]], [[2p5e|2P5E]], [[2p5w|2P5W]], [[2pye|2PYE]], [[2bnr|2BNR]]
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2pyf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pyf OCA], [http://www.ebi.ac.uk/pdbsum/2pyf PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2pyf RCSB]</span>
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== Disease ==
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}}
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[https://www.uniprot.org/uniprot/TRAC_HUMAN TRAC_HUMAN] TCR-alpha-beta-positive T-cell deficiency. The disease is caused by variants affecting the gene represented in this entry.
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== Function ==
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[https://www.uniprot.org/uniprot/TRAC_HUMAN TRAC_HUMAN] Constant region of T cell receptor (TR) alpha chain (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).<ref>PMID:15040585</ref> <ref>PMID:23524462</ref> <ref>PMID:24600447</ref> <ref>PMID:25493333</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/py/2pyf_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2pyf ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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'''Crystal Structures of High Affinity Human T-Cell Receptors Bound to pMHC RevealNative Diagonal Binding Geometry Unbound TCR Clone 5-1'''
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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<ref>PMID:17644531</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2pyf" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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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.
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*[[T-cell receptor 3D structures|T-cell receptor 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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2PYF is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PYF OCA].
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__TOC__
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</StructureSection>
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==Reference==
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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:[http://www.ncbi.nlm.nih.gov/pubmed/17644531 17644531]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Protein complex]]
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[[Category: Large Structures]]
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[[Category: Baston, E.]]
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[[Category: Baston E]]
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[[Category: Boulter, J M.]]
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[[Category: Boulter JM]]
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[[Category: Dunn, S.]]
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[[Category: Dunn S]]
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[[Category: Gao, F.]]
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[[Category: Gao F]]
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[[Category: Jakobsen, B K.]]
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[[Category: Jakobsen BK]]
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[[Category: Li, Y.]]
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[[Category: Li Y]]
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[[Category: Molloy, P.]]
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[[Category: Molloy P]]
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[[Category: Moysey, R.]]
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[[Category: Moysey R]]
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[[Category: Rizkallah, P J.]]
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[[Category: Rizkallah PJ]]
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[[Category: Sami, M.]]
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[[Category: Sami M]]
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[[Category: Todorov, P.]]
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[[Category: Todorov P]]
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[[Category: Vuidepot, A.]]
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[[Category: Vuidepot A]]
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[[Category: cdr3]]
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[[Category: high affinity]]
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[[Category: immune system]]
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[[Category: mutant]]
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[[Category: ny-eso-1]]
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[[Category: phage display]]
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[[Category: t-cell receptor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:42:23 2008''
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Current revision

Crystal Structures of High Affinity Human T-Cell Receptors Bound to pMHC RevealNative Diagonal Binding Geometry Unbound TCR Clone 5-1

PDB ID 2pyf

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