6at9: Difference between revisions
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==Crystal structure of an anaplastic lymphoma kinase-derived neuroblastoma tumor antigen bound to the Human Major Histocompatibility Complex Class I molecule HLA-A*0101== | ==Crystal structure of an anaplastic lymphoma kinase-derived neuroblastoma tumor antigen bound to the Human Major Histocompatibility Complex Class I molecule HLA-A*0101== | ||
<StructureSection load='6at9' size='340' side='right' caption='[[6at9]], [[Resolution|resolution]] 2.95Å' scene=''> | <StructureSection load='6at9' size='340' side='right'caption='[[6at9]], [[Resolution|resolution]] 2.95Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6at9]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AT9 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[6at9]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AT9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6AT9 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6at9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6at9 OCA], [http://pdbe.org/6at9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6at9 RCSB], [http://www.ebi.ac.uk/pdbsum/6at9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6at9 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6at9" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6at9" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta-2 microglobulin 3D structures|Beta-2 microglobulin 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Haussler, D]] | [[Category: Haussler, D]] | ||
[[Category: Rao, A A]] | [[Category: Rao, A A]] | ||
Revision as of 00:31, 29 October 2020
Crystal structure of an anaplastic lymphoma kinase-derived neuroblastoma tumor antigen bound to the Human Major Histocompatibility Complex Class I molecule HLA-A*0101Crystal structure of an anaplastic lymphoma kinase-derived neuroblastoma tumor antigen bound to the Human Major Histocompatibility Complex Class I molecule HLA-A*0101
Structural highlights
Disease[B2MG_HUMAN] Defects in B2M are the cause of hypercatabolic hypoproteinemia (HYCATHYP) [MIM:241600]. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation.[1] 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.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Function[1A01_HUMAN] Involved in the presentation of foreign antigens to the immune system. [B2MG_HUMAN] Component of the class I major histocompatibility complex (MHC). Involved in the presentation of peptide antigens to the immune system. Publication Abstract from PubMedThe identification of recurrent human leukocyte antigen (HLA) neoepitopes driving T cell responses against tumors poses a significant bottleneck in the development of approaches for precision cancer therapeutics. Here, we employ a bioinformatics method, Prediction of T Cell Epitopes for Cancer Therapy, to analyze sequencing data from neuroblastoma patients and identify a recurrent anaplastic lymphoma kinase mutation (ALK R1275Q) that leads to two high affinity neoepitopes when expressed in complex with common HLA alleles. Analysis of the X-ray structures of the two peptides bound to HLA-B*15:01 reveals drastically different conformations with measurable changes in the stability of the protein complexes, while the self-epitope is excluded from binding due to steric hindrance in the MHC groove. To evaluate the range of HLA alleles that could display the ALK neoepitopes, we used structure-based Rosetta comparative modeling calculations, which accurately predict several additional high affinity interactions and compare our results with commonly used prediction tools. Subsequent determination of the X-ray structure of an HLA-A*01:01 bound neoepitope validates atomic features seen in our Rosetta models with respect to key residues relevant for MHC stability and T cell receptor recognition. Finally, MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes are recognized by CD8+ T cells. This work provides a rational approach toward high-throughput identification and further optimization of putative neoantigen/HLA targets with desired recognition features for cancer immunotherapy. A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations.,Toor JS, Rao AA, McShan AC, Yarmarkovich M, Nerli S, Yamaguchi K, Madejska AA, Nguyen S, Tripathi S, Maris JM, Salama SR, Haussler D, Sgourakis NG Front Immunol. 2018 Jan 30;9:99. doi: 10.3389/fimmu.2018.00099. eCollection 2018. PMID:29441070[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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