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

Summary for 6AT9

• Entry DOI: 10.2210/pdb6at9/pdb
• Descriptor: HLA class I histocompatibility antigen, A-1 alpha chain, Beta-2-microglobulin, ALK (3 entities in total)
• Functional Keywords: lymphoma kinase-derived neuroblastoma tumor antigen, human major histocompatibility complex class i, mhc-i, complex, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P30443; Secreted . Note=(Microbial infection) In the presence of M: P61769
• Total number of polymer chains: 3
• Total formula weight: 45697.67

Authors

Toor, J.,Rao, A.A.,Salama, S.,Tripathi, S.,Haussler, D.,Sgourakis, N.G. (deposition date: 2017-08-28, release date: 2018-03-21, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.9503 Å)