6AT9

Crystal structure of an anaplastic lymphoma kinase-derived neuroblastoma tumor antigen bound to the Human Major Histocompatibility Complex Class I molecule HLA-A*0101

6AT9 の概要

• エントリーDOI: 10.2210/pdb6at9/pdb
• 分子名称: HLA class I histocompatibility antigen, A-1 alpha chain, Beta-2-microglobulin, ALK (3 entities in total)
• 機能のキーワード: lymphoma kinase-derived neuroblastoma tumor antigen, human major histocompatibility complex class i, mhc-i, complex, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P30443; Secreted . Note=(Microbial infection) In the presence of M: P61769
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 45697.67

構造登録者

Toor, J.,Rao, A.A.,Salama, S.,Tripathi, S.,Haussler, D.,Sgourakis, N.G. (登録日: 2017-08-28, 公開日: 2018-03-21, 最終更新日: 2024-11-06)

主引用文献

Toor, J.S.,Rao, A.A.,McShan, A.C.,Yarmarkovich, M.,Nerli, S.,Yamaguchi, K.,Madejska, A.A.,Nguyen, S.,Tripathi, S.,Maris, J.M.,Salama, S.R.,Haussler, D.,Sgourakis, N.G.
A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations.
Front Immunol, 9:99-99, 2018

PubMed Abstract: The 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 ( 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 neoepitopes, we used structure-based 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 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.

PubMed: 29441070
DOI: 10.3389/fimmu.2018.00099

実験手法

X-RAY DIFFRACTION (2.9503 Å)