Figure 2. The TCR uses multiple mechanisms to engage numerous peptide–MHC molecules.

a | Macro-level changes enable the T cell receptor (TCR) to bind to peptide–MHC complexes with an altered peptide binding angle (red dotted line) and/or peptide binding register (black dotted line) within a roughly diagonal binding mode³⁸. The cartoon shows 'footprints' of the TCR complementarity-determining region (CDR) loops projected down onto the peptide–MHC platform. b | Micro-level CDR loop flexibility enables the accommodation of different peptide–MHC 'landscapes'. The cartoon shows a side view of a TCR engaging a peptide–MHC complex. c | Structural studies show that most TCRs focus on two to four upward-facing peptide residues. In this example, the TCR is focused on the two peptide residues shown in red. Such residue-focused interaction allows the TCR to tolerate multiple amino acid substitutions at other positions in the peptide (indicated by different colours). The above examples are not mutually exclusive and represent only some of the possibilities. MHC-binding motifs often allow for different residues at primary MHC anchors⁴⁹. It should also be noted that TCRs can change the conformation of the peptide–MHC complex following engagement^34,35,36.