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2j8u

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(New page: 200px<br /> <applet load="2j8u" size="450" color="white" frame="true" align="right" spinBox="true" caption="2j8u, resolution 2.88&Aring;" /> '''LARGE CDR3A LOOP AL...)
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[[Image:2j8u.gif|left|200px]]<br />
 
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<applet load="2j8u" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2j8u, resolution 2.88&Aring;" />
 
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'''LARGE CDR3A LOOP ALTERATION AS A FUNCTION OF MHC MUTATION.'''<br />
 
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==Overview==
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==Large CDR3a loop alteration as a function of MHC mutation.==
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The keystone of the adaptive immune response is T cell receptor (TCR), recognition of peptide presented by major histocompatibility complex, (pMHC) molecules. The crystal structure of AHIII TCR bound to MHC, HLA-A2, showed a large interface with an atypical binding orientation. MHC, mutations in the interface of the proteins were tested for changes in TCR, recognition. From the range of responses observed, three representative, HLA-A2 mutants, T163A, W167A, and K66A, were selected for further study., Binding constants and co-crystal structures of the AHIII TCR and the three, mutants were determined. K66 in HLA-A2 makes contacts with both peptide, and TCR, and has been identified as a critical residue for recognition by, numerous TCR. The K66A mutation resulted in the lowest AHIII T cell, response and the lowest binding affinity, which suggests that the T cell, response may correlate with affinity. Importantly, the K66A mutation does, not affect the conformation of the peptide. The change in affinity appears, to be due to a loss in hydrogen bonds in the interface as a result of a, conformational change in the TCR complementarity-determining region 3, (CDR3) loop. Isothermal titration calorimetry confirmed the loss of, hydrogen bonding by a large loss in enthalpy. Our findings are, inconsistent with the notion that the CDR1 and CDR2 loops of the TCR are, responsible for MHC restriction, while the CDR3 loops interact solely with, the peptide. Instead, we present here an MHC mutation that does not change, the conformation of the peptide, yet results in an altered conformation of, a CDR3.
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<StructureSection load='2j8u' size='340' side='right'caption='[[2j8u]], [[Resolution|resolution]] 2.88&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2j8u]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J8U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2J8U FirstGlance]. <br>
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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]] 2.88&#8491;</td></tr>
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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=2j8u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j8u OCA], [https://pdbe.org/2j8u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2j8u RCSB], [https://www.ebi.ac.uk/pdbsum/2j8u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2j8u ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:[https://omim.org/entry/241600 241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.<ref>PMID:16549777</ref> Note=Beta-2-microglobulin may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. Persistently high beta(2)-microglobulin serum levels lead to amyloidosis in patients on long-term hemodialysis.<ref>PMID:3532124</ref> <ref>PMID:1336137</ref> <ref>PMID:7554280</ref> <ref>PMID:4586824</ref> <ref>PMID:8084451</ref> <ref>PMID:12119416</ref> <ref>PMID:12796775</ref> <ref>PMID:16901902</ref> <ref>PMID:16491088</ref> <ref>PMID:17646174</ref> <ref>PMID:18835253</ref> <ref>PMID:18395224</ref> <ref>PMID:19284997</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system.
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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/j8/2j8u_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=2j8u 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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The keystone of the adaptive immune response is T cell receptor (TCR) recognition of peptide presented by major histocompatibility complex (pMHC) molecules. The crystal structure of AHIII TCR bound to MHC, HLA-A2, showed a large interface with an atypical binding orientation. MHC mutations in the interface of the proteins were tested for changes in TCR recognition. From the range of responses observed, three representative HLA-A2 mutants, T163A, W167A, and K66A, were selected for further study. Binding constants and co-crystal structures of the AHIII TCR and the three mutants were determined. K66 in HLA-A2 makes contacts with both peptide and TCR, and has been identified as a critical residue for recognition by numerous TCR. The K66A mutation resulted in the lowest AHIII T cell response and the lowest binding affinity, which suggests that the T cell response may correlate with affinity. Importantly, the K66A mutation does not affect the conformation of the peptide. The change in affinity appears to be due to a loss in hydrogen bonds in the interface as a result of a conformational change in the TCR complementarity-determining region 3 (CDR3) loop. Isothermal titration calorimetry confirmed the loss of hydrogen bonding by a large loss in enthalpy. Our findings are inconsistent with the notion that the CDR1 and CDR2 loops of the TCR are responsible for MHC restriction, while the CDR3 loops interact solely with the peptide. Instead, we present here an MHC mutation that does not change the conformation of the peptide, yet results in an altered conformation of a CDR3.
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==Disease==
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Single MHC mutation eliminates enthalpy associated with T cell receptor binding.,Miller PJ, Pazy Y, Conti B, Riddle D, Appella E, Collins EJ J Mol Biol. 2007 Oct 19;373(2):315-27. Epub 2007 Jul 26. PMID:17825839<ref>PMID:17825839</ref>
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Known diseases associated with this structure: Abacavir hypersensitivity, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142800 142800]], Ankylosing spondylitis, susceptibility to, 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142800 142800]], Hypoproteinemia, hypercatabolic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=109700 109700]], Stevens-Johnson syndrome, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=142800 142800]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2J8U is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2J8U OCA].
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</div>
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<div class="pdbe-citations 2j8u" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Single MHC Mutation Eliminates Enthalpy Associated with T Cell Receptor Binding., Miller PJ, Pazy Y, Conti B, Riddle D, Appella E, Collins EJ, J Mol Biol. 2007 Jul 26;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17825839 17825839]
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*[[Beta-2 microglobulin 3D structures|Beta-2 microglobulin 3D structures]]
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*[[MHC 3D structures|MHC 3D structures]]
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*[[MHC I 3D structures|MHC I 3D structures]]
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*[[T-cell receptor 3D structures|T-cell receptor 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
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[[Category: Protein complex]]
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[[Category: Benhar YP]]
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[[Category: Benhar, Y.P.]]
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[[Category: Biddison W]]
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[[Category: Biddison, W.]]
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[[Category: Collins EJ]]
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[[Category: Collins, E.J.]]
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[[Category: Miller PJ]]
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[[Category: Miller, P.J.]]
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[[Category: class i mhc-tcr co-crystal]]
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[[Category: disease mutation]]
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[[Category: glycation]]
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[[Category: glycoprotein]]
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[[Category: host-virus interaction]]
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[[Category: immune response]]
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[[Category: immune system]]
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[[Category: immunoglobulin domain]]
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[[Category: imunoregulatory complex]]
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[[Category: membrane]]
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[[Category: mhc i]]
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[[Category: polymorphism]]
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[[Category: pyrrolidone carboxylic acid]]
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[[Category: secreted]]
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[[Category: transmembrane]]
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[[Category: ubl conjugation]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:53:06 2007''
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Current revision

Large CDR3a loop alteration as a function of MHC mutation.

PDB ID 2j8u

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