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2gtw

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Human Class I MHC HLA-A2 in complex with the nonameric Melan-A/MART-1(27-35) peptide having A27L substitution

Structural highlights

2gtw is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.548Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MAR1_HUMAN Involved in melanosome biogenesis by ensuring the stability of GPR143. Plays a vital role in the expression, stability, trafficking, and processing of melanocyte protein PMEL, which is critical to the formation of stage II melanosomes.^[1] ^[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Small structural changes in peptides presented by major histocompatibility complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to antigen structure. Yet there are striking examples of TCR recognition of structurally dissimilar ligands. The resulting unpredictability of how T cells will respond to different or modified antigens impacts both our understanding of the physical bases for TCR specificity as well as efforts to engineer peptides for immunomodulation. In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely used as clinical vaccines. Two overlapping epitopes spanning amino acid residues 26 through 35 are of particular interest: numerous clinical studies have been performed using variants of the MART-1 26-35 decamer, although only the 27-35 nonamer has been found on the surface of targeted melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1(26/27-35)-reactive T cells show broad cross-reactivity towards these ligands. Simultaneously, however, many of the cross-reactive T cells remain unable to recognize anchor-modified variants with very subtle structural differences. These dichotomous observations challenge our thinking about how structural information on unligated peptide/MHC complexes should be best used when addressing questions of TCR specificity. Our findings also indicate that caution is warranted in the design of immunotherapeutics based on the MART-1 26/27-35 epitopes, as neither cross-reactivity nor selectivity is predictable based on the analysis of the structures alone.

Structures of MART-126/27-35 Peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition.,Borbulevych OY, Insaidoo FK, Baxter TK, Powell DJ Jr, Johnson LA, Restifo NP, Baker BM J Mol Biol. 2007 Oct 5;372(5):1123-36. Epub 2007 Jul 26. PMID:17719062^[3]

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

References

↑ Hoashi T, Watabe H, Muller J, Yamaguchi Y, Vieira WD, Hearing VJ. MART-1 is required for the function of the melanosomal matrix protein PMEL17/GP100 and the maturation of melanosomes. J Biol Chem. 2005 Apr 8;280(14):14006-16. Epub 2005 Jan 28. PMID:15695812 doi:10.1074/jbc.M413692200
↑ Giordano F, Bonetti C, Surace EM, Marigo V, Raposo G. The ocular albinism type 1 (OA1) G-protein-coupled receptor functions with MART-1 at early stages of melanogenesis to control melanosome identity and composition. Hum Mol Genet. 2009 Dec 1;18(23):4530-45. doi: 10.1093/hmg/ddp415. Epub 2009 Aug , 28. PMID:19717472 doi:10.1093/hmg/ddp415
↑ Borbulevych OY, Insaidoo FK, Baxter TK, Powell DJ Jr, Johnson LA, Restifo NP, Baker BM. Structures of MART-126/27-35 Peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition. J Mol Biol. 2007 Oct 5;372(5):1123-36. Epub 2007 Jul 26. PMID:17719062 doi:10.1016/j.jmb.2007.07.025

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2gtw"

Categories: Homo sapiens | Large Structures | Baker BM | Borbulevych OY

@@ Line 3: / Line 3: @@
 <StructureSection load='2gtw' size='340' side='right'caption='[[2gtw]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2gtw]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GTW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GTW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2gtw]] is a 6 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=2GTW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GTW FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.548&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1jf1|1jf1]], [[1jht|1jht]], [[2gt9|2gt9]], [[2gtz|2gtz]], [[2guo|2guo]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HLA-A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), B2M ([https://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'>[https://proteopedia.org/fgij/fg.htm?mol=2gtw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gtw OCA], [https://pdbe.org/2gtw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gtw RCSB], [https://www.ebi.ac.uk/pdbsum/2gtw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gtw ProSAT]</span></td></tr>
 </table>
-== Disease ==
-[[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>
 == Function ==
-[[https://www.uniprot.org/uniprot/1A02_HUMAN 1A02_HUMAN]] Involved in the presentation of foreign antigens to the immune system. [[https://www.uniprot.org/uniprot/MAR1_HUMAN MAR1_HUMAN]] Involved in melanosome biogenesis by ensuring the stability of GPR143. Plays a vital role in the expression, stability, trafficking, and processing of melanocyte protein PMEL, which is critical to the formation of stage II melanosomes.<ref>PMID:15695812</ref> <ref>PMID:19717472</ref>  [[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.
+[https://www.uniprot.org/uniprot/MAR1_HUMAN MAR1_HUMAN] Involved in melanosome biogenesis by ensuring the stability of GPR143. Plays a vital role in the expression, stability, trafficking, and processing of melanocyte protein PMEL, which is critical to the formation of stage II melanosomes.<ref>PMID:15695812</ref> <ref>PMID:19717472</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 36: / Line 33: @@
 *[[Beta-2 microglobulin 3D structures|Beta-2 microglobulin 3D structures]]
 *[[MHC 3D structures|MHC 3D structures]]
+*[[MHC I 3D structures|MHC I 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Baker, B M]]
+[[Category: Baker BM]]
-[[Category: Borbulevych, O Y]]
+[[Category: Borbulevych OY]]
-[[Category: A27l mutation]]
-[[Category: Cancer vaccine]]
-[[Category: Hla-a2]]
-[[Category: Immune system]]
-[[Category: Melan-a/mart-1 peptide]]
-[[Category: Melanoma]]
-[[Category: Mhc class i]]
-[[Category: Nonapeptide]]

2gtw

From Proteopedia

Current revision

Human Class I MHC HLA-A2 in complex with the nonameric Melan-A/MART-1(27-35) peptide having A27L substitution

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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