Fig. 1. Structural modeling and interaction between TCR-targeting antibodies and TRBC1/2.

a Homology between human TRBC1 and TRBC2. Numbering according to constant region of proteins (TRBC1, UniProtKB - P01850 and TRBC2, UniProtKB - A0A5B9) Corresponding positions of amino acids from the β chain of the A6 TCR used in this study are also shown. b Superimposition of HuJovi-1 Fab-TCR complex on TCR CD3 complex structure showing how specificity for TRBC is mediated in the context of the CD3 sheath. Right: Close-up of the interface between TCR complex and HuJovi-1 Fab. The Fab heavy and light chains are shown in green and gray, respectively. Despite proximity to CD3ε (yellow), neither the heavy nor the light chains form appropriate shape complementarity to interact with the CD3ε subunit of the TCR complex. c Molecular interface of the interaction between HuJovi-1 and TRBC1 (PDB ID 7AMP). Three key amino acids (Thr28, Tyr32, and Tyr98) within HuJovi-1 drive the specificity for TRBC1 (all antibody aa positions are referring to Kabat numbering scheme¹²). Thr28 of HuJovi-1 mediates contact with Lys119, while Tyr32 mediates contact with Asn119. Tyr98 lies across the binding pocket and forms interactions with both Asn119 and Lys120. d Interaction between HuJovi-1 and TRBC2 (PDB ID 7AMQ). Inversion of Lys and Asn at positions 119 and 120 of the TCR β-chain removes the interacting partners of Thr28 and Ty32 in the antibody.