Figure 2

The TCRm binds centrally over the AFP/HLA-A*02 complex engaging the full length of the AFP peptide. (A) Overview of the TCRm-AFP/HLA-A*02 complex with the heavy and light chains of the TCRm, the HLA-A*02 heavy chain, peptide, and β₂-microglobulin colored as indicated. This color scheme is maintained throughout the figure. (B) The TCRm and its CDR loops are positioned centrally over AFP/HLA-A*02, forming a diagonal binding mode mimicking that formed by naturally occurring αβ TCRs. The CDR loops are indicated, and black circles indicate the centers of mass of the VH and VL domains. (C) TCRm contacts to the peptide are formed by CDR1H, CDR2H, CDR3L, and CDR1L. Contacts from each loop to each peptide amino acid are indicated by lines. The number of contacts is shown by the numbers across the top and represented by line width. Red lines indicate the presence of one or more hydrogen bond or salt bridge. The impact of alanine substitutions at the various peptide positions on TCRm recognition, taken from Ref.¹³, is indicated by the symbols underneath the peptide amino acids. (D) Illustration of how the TCRm packs against the peptide, reflecting engagement across the peptide length. (E) TCRm contacts to AFP/HLA-A*02 mapped to the surface of the molecule. The number of contacts to each amino acid is indicated by purple-white color scale. The peptide surface is outlined by the green line. Substantially more contacts are made to the HLA-A*02 α1 helix compared to the α2 helix. (F) The TCRm interacts with the HLA-A*02 α1 helix via a series of interdigitating side chains that form multiple electrostatic interactions with polymorphic sites as indicated by the dashed red lines.