Fluorine substitutions in an antigenic peptide selectively modulate T-cell receptor binding in a minimally perturbing manner

Abstract

Synopsis T cell receptor (TCR) recognition of antigenic peptides bound and presented by major histocompatibility complex (MHC) molecules forms the basis of the cellular immune response to pathogens and cancer. TCRs bind peptide/MHC molecules weakly and with fast kinetics, features which have hindered detailed biophysical studies of these interactions. Modified peptides resulting in enhanced TCR binding could help overcome these challenges. Further, there is considerable interest in using modified peptides with enhanced TCR binding as the basis for clinical vaccines. Here, we studied how fluorine substitutions in an antigenic peptide can selectively impact TCR recognition. Using a structure-guided design approach, we found that fluorination of the HTLV-1 Tax11-19 peptide (Tax) enhanced binding by the Tax-specific TCR A6, yet weakened binding by the Tax-specific TCR B7. The changes in affinity were consistent with crystallographic structures and fluorine chemistry, and with A6, independent of other substitutions in the interface. Peptide fluorination thus provides a means to selectively modulate TCR binding affinity without significantly perturbing peptide composition or structure. Lastly, in probing the mechanism of fluorine’s effect on TCR binding, our data were most consistent with fluorine’s unique “polar hydrophobicity,” a finding which should impact other attempts to alter molecular recognition with fluorine.

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

“…These findings are of interest given the common approach of modifying select positions to enhance peptide binding to MHC proteins or to alter recognition by T cell receptors. 30–31 Such modifications have in some cases unexpectedly altered peptide motion. 2,4 peptide conformation, 20 and T cell recognition, 32 and our findings reveal these effects can occur via through-peptide and through-protein mechanisms.…”

Fluorine–Protein Interactions and 19F NMR Isotropic Chemical Shifts: An Empirical Correlation with Implications for Drug Design

“…[purple] and difluoro 3,4-fluoro Phe in 3d3v [green]) bound to A6 T-cell receptor (TCR) and human leukocyte antigen (HLA)-A2 [43] as shown in Figure 9. The fluorine of 4-fluoro Phe is 3.83 from the oxygen of Ser 31, a distance which is too great to enable formation of a hydrogen bond.…”

Disparate Degrees of Hypervariable Loop Flexibility Control T-Cell Receptor Cross-Reactivity, Specificity, and Binding Mechanism

“…These include the Tax peptide (LLFGYPVYV) 16 , the HuD peptide (LGYGFVNYI) 17 , the Tel1p peptide (MLWGYLQYV) 18 , and six single amino acid variants of the Tax peptide 19; 20; 21 , all presented by the class I MHC HLA-A*0201 (HLA-A2). These structures comprise the largest structural database available for a single TCR.…”