Comparative Analysis of the CDR Loops of Antigen Receptors

Abstract

The adaptive immune system uses two main types of antigen receptors: T-cell receptors (TCRs) and antibodies. While both proteins share a globally similar β-sandwich architecture, TCRs are specialized to recognize peptide antigens in the binding groove of the major histocompatibility complex, while antibodies can bind an almost infinite range of molecules. For both proteins, the main determinants of target recognition are the complementarity-determining region (CDR) loops. Five of the six CDRs adopt a limited number of backbone conformations, known as the “canonical classes”; the remaining CDR (β3in TCRs and H3 in antibodies) is more structurally diverse. In this paper, we first update the definition of canonical forms in TCRs, build an auto-updating sequence-based prediction tool (available at http://opig.stats.ox.ac.uk/resources) and demonstrate its application on large scale sequencing studies. Given the global similarity of TCRs and antibodies, we then examine the structural similarity of their CDRs. We find that TCR and antibody CDRs tend to have different length distributions, and where they have similar lengths, they mostly occupy distinct structural spaces. In the rare cases where we found structural similarity, the underlying sequence patterns for the TCR and antibody version are different. Finally, where multiple structures have been solved for the same CDR sequence, the structural variability in TCR loops is higher than that in antibodies, suggesting TCR CDRs are more flexible. These structural differences between TCR and antibody CDRs may be important to their different biological functions.

T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions

“…Additionally, a characterization of structure and dynamics of a TCR is essential to elucidate the antigen-binding mechanism, the involved conformational changes and the associated biological implications ( 4 , 17 , 18 ). X-ray studies comparing TCRs crystallized with and without the pMHC complex revealed a high flexibility in the binding interface ( 1 , 3 , 14 , 17 , 20 ). However, crystal structures represent only a snapshot of a specific protein conformation that can be distorted due to crystal packing effects ( 15 , 59 ).…”

“…Depending on the type of the T-cell the TCR is expressed on, it recognizes protein fragments derived from intra- or extracellular regions, displayed by the Major Histocompatibility Complex (MHC) ( 2 ). TCRs consist of an α and a β chain analogous to the heavy and light chain in the antigen-binding fragment (Fab) of antibodies ( 3 , 4 ). Vα and Cα can be interpreted as homologous in sequence and structure to the V L and C L domains in antibodies as well as Vβ and Cβ as equivalent to V H and C H ( 5 , 6 ).…”

“…TCR alpha chains are made by V and J genes, while beta chains are produced by V, D, and J genes. Sequence and structural diversity are concentrated on six hypervariable loops, also known as the complementarity determining regions (CDRs) ( 3 , 8 , 9 ). The CDR3α loop reveals a diversity of length and sequence composition due to the recombination of two gene segments V and J, while the CDR3β loop variability is increased due to the D gene ( 10 , 11 ).…”

“…Due to the high variability in sequence, length and the ability of the CDR3 loops to adopt different conformations during the V(D)J recombination, structure prediction remains challenging ( 15 , 16 ). Compared to antibodies only few studies focused on characterizing and classifying TCR CDR loops into canonical classes ( 3 , 9 ). Crystal structures of the same TCRs crystallized with and without pMHC (peptides presented by MHC molecules) reveal conformational changes upon binding mainly in the CDR3 loops ( 12 , 17 , 18 ).…”

Development of a Structure-based Computational Simulation to Optimize the Blocking Efficacy of Pro-antibodies

“…However, 30% of pro-Abs did not achieve the blocking ability to even 50-fold compared to parental Abs. The reason for the low blocking ability is that there are distinct differences among the complementarity-determining region (CDR) loop of each Ab, [20,21] so the identical linker of the Ab lock cannot be applied to every Ab. In order to overcome this issue, it is essential to design a method to predict and optimize the Ab lock with a suitable linker for each Ab.…”