title: Structures of native and affinity-enhanced WT1 epitopes bound to HLA-A*0201: implications for WT1-based cancer therapeutics.
abstract: Presentation of peptides by class I or class II major histocompatibility complex (MHC) molecules is required for the initiation and propagation of a T cell-mediated immune response. Peptides from the Wilms Tumor 1 transcription factor (WT1), upregulated in many hematopoetic and solid tumors, can be recognized by T cells and numerous efforts are underway to engineer WT1-based cancer vaccines. Here we determined the structures of the class I MHC molecule HLA-A*0201 bound to the native 126-134 epitope of the WT1 peptide and a recently described variant (R1Y) with improved MHC binding. The R1Y variant, a potential vaccine candidate, alters the positions of MHC charged side chains near the peptide N-terminus and significantly reduces the peptide/MHC electrostatic surface potential. These alterations indicate that the R1Y variant is an imperfect mimic of the native WT1 peptide, and suggest caution in its use as a therapeutic vaccine. Stability measurements revealed how the R1Y substitution enhances MHC binding affinity, and together with the structures suggest a strategy for engineering WT1 variants with improved MHC binding that retain the structural features of the native peptide/MHC complex.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556, United States.
authors.forename: Oleg Y
authors.initials: OY
authors.lastname: Borbulevych
authors.forename: Priscilla
authors.initials: P
authors.lastname: Do
authors.forename: Brian M
authors.initials: BM
authors.lastname: Baker
mesh_terms: D017951:Antigen Presentation; D019496:Cancer Vaccines; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D015234:HLA-A Antigens / Q000737:chemistry* / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D015202:Protein Engineering; D055550:Protein Stability; D055672:Static Electricity; D013329:Structure-Activity Relationship; D025721:WT1 Proteins / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use
chemical_list: D019496:Cancer Vaccines; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; C543100:WT1 (126-134), human; D025721:WT1 Proteins