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5brz

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Revision as of 06:05, 7 June 2023

MAGE-A3 reactive TCR in complex with MAGE-A3 in HLA-A1

Structural highlights

5brz is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MAGA3_HUMAN Proposed to enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases. May enhance ubiquitin ligase activity of TRIM28 and stimulate p53/TP53 ubiquitination by TRIM28. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. May play a role in embryonal development and tumor transformation or aspects of tumor progression. In vitro promotes cell viability in melanoma cell lines. Antigen recognized on a melanoma by autologous cytolytic T-lymphocytes.^[1]

Publication Abstract from PubMed

Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self-antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics.

Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy.,Raman MC, Rizkallah PJ, Simmons R, Donnellan Z, Dukes J, Bossi G, Le Provost GS, Todorov P, Baston E, Hickman E, Mahon T, Hassan N, Vuidepot A, Sami M, Cole DK, Jakobsen BK Sci Rep. 2016 Jan 13;6:18851. doi: 10.1038/srep18851. PMID:26758806^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Doyle JM, Gao J, Wang J, Yang M, Potts PR. MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell. 2010 Sep 24;39(6):963-74. PMID:20864041 doi:10.1016/j.molcel.2010.08.029
↑ Raman MC, Rizkallah PJ, Simmons R, Donnellan Z, Dukes J, Bossi G, Le Provost GS, Todorov P, Baston E, Hickman E, Mahon T, Hassan N, Vuidepot A, Sami M, Cole DK, Jakobsen BK. Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy. Sci Rep. 2016 Jan 13;6:18851. doi: 10.1038/srep18851. PMID:26758806 doi:http://dx.doi.org/10.1038/srep18851

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5brz"

@@ Line 3: / Line 3: @@
 <StructureSection load='5brz' size='340' side='right'caption='[[5brz]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5brz]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BRZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BRZ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5brz]] is a 5 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=5BRZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BRZ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5bs0|5bs0]]</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5brz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5brz OCA], [https://pdbe.org/5brz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5brz RCSB], [https://www.ebi.ac.uk/pdbsum/5brz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5brz ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HLA-A, HLAA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), B2M, CDABP0092, HDCMA22P ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), TRAC, TCRA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), B2M, HDCMA22P ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5brz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5brz OCA], [http://pdbe.org/5brz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5brz RCSB], [http://www.ebi.ac.uk/pdbsum/5brz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5brz ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[http://www.uniprot.org/uniprot/B2MG_HUMAN B2MG_HUMAN]] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:[http://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>
 == Function ==
-[[http://www.uniprot.org/uniprot/1A01_HUMAN 1A01_HUMAN]] Involved in the presentation of foreign antigens to the immune system. [[http://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.
+[https://www.uniprot.org/uniprot/MAGA3_HUMAN MAGA3_HUMAN] Proposed to enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases. May enhance ubiquitin ligase activity of TRIM28 and stimulate p53/TP53 ubiquitination by TRIM28. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. May play a role in embryonal development and tumor transformation or aspects of tumor progression. In vitro promotes cell viability in melanoma cell lines. Antigen recognized on a melanoma by autologous cytolytic T-lymphocytes.<ref>PMID:20864041</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 30: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Bossi, G]]
+[[Category: Bossi G]]
-[[Category: Cole, D K]]
+[[Category: Cole DK]]
-[[Category: Donnellan, Z]]
+[[Category: Donnellan Z]]
-[[Category: Dukes, J]]
+[[Category: Dukes J]]
-[[Category: Hassan, N]]
+[[Category: Hassan N]]
-[[Category: Hickman, E]]
+[[Category: Hickman E]]
-[[Category: Jakobsen, B K]]
+[[Category: Jakobsen BK]]
-[[Category: LeProvost, G]]
+[[Category: LeProvost G]]
-[[Category: LomaX, M]]
+[[Category: LomaX M]]
-[[Category: Mahon, T]]
+[[Category: Mahon T]]
-[[Category: Oates, J]]
+[[Category: Oates J]]
-[[Category: Raman, M C.C]]
+[[Category: Raman MCC]]
-[[Category: Rizkallah, P J]]
+[[Category: Rizkallah PJ]]
-[[Category: Sami, M]]
+[[Category: Sami M]]
-[[Category: Simmons, R]]
+[[Category: Simmons R]]
-[[Category: Vuidepot, A]]
+[[Category: Vuidepot A]]
-[[Category: Immune system]]
-[[Category: Immuno pmhc tcr mage]]

5brz

From Proteopedia

Revision as of 06:05, 7 June 2023

MAGE-A3 reactive TCR in complex with MAGE-A3 in HLA-A1

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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