Crystal Structures of HLA-A*0201 Complexed with Melan-A/MART-1_26(27L)-35 Peptidomimetics Reveal Conformational Heterogeneity and Highlight Degeneracy of T Cell Recognition

Abstract

There is growing interest in using tumor associated antigens presented by class-I major histocompatibility complex (MHC-I) proteins as cancer vaccines. As native peptides are poorly stable in biological fluids, researchers have sought to engineer synthetic peptidomimetics with greater biostability. Here, we demonstrate that antigenic peptidomimetics of the Melan-A/ MART-1 26(27L)-35 melanoma antigen adopt strikingly different conformations when bound to MHC-I, highlighting the degeneracy of T cell recognition and revealing the challenges associated with mimicking native peptide conformation.

Structural insights into the binding of hepatitis B virus core peptide to HLA‐A2 alleles: Towards designing better vaccines

“…A recent study of the melanoma Melan‐A/MART‐126(27L)‐35 antigen showed enhanced HLA‐A2‐restricted immunogenicity with protease resistance, after substitution of the central aas of the antigenic peptide 13. Such improvements in immunogenicity may also be possible, given the new data we have generated for HLA‐A2 alleles.…”

Structural and dynamic control of T‐cell receptor specificity, cross‐reactivity, and binding mechanism

“…We have hypothesized that a more robust anti‐tumor immune response could be generated with T cells more explicitly ‘focused’ on the decamer, but without a stronger HLA‐A2 binding nonameric peptide, this hypothesis cannot easily be tested. As the dynamic consequences of altering the 27–35 nonamer appear to stem from modification of the P2 anchor, one avenue forward may be to utilize non‐natural amino acids and/or chemical synthesis of ‘peptidomimetics’ to generate a more immunogenic MART‐1 nonameric variant .…”

Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

“…For example, a peptide, ELA‐2.1, was designed to mimic the conformation of a melanoma antigen bound to major histocompatibility complex‐I. This antigen mimic includes a β‐alanine in place of a glutamic acid at its N‐terminus, and a modified amino acid 3‐aminomethyl benzoic acid (3AZ), used as a synthetic spacer to enhance protease resistance (PDB ID 3o3e, Figure ) . Compared to the native peptide structure, the β‐alanine is in a folded conformation ( θ = 65°) and forms a hydrogen‐bond with a Lysine at the edge of the MHC binding cleft, The rigid conformation of 3AZ is accommodated in the helical structure of the antigen peptide, but moves a portion of the peptide away from the floor of peptide binding cleft of the MHC molecule, and facilitates antigen recognition by the T‐cell receptor …”

“…Ball and stick structure of engineered melanoma tumor antigen, containing an N‐terminal β‐alanine residue (BAL, green) and 3‐aminomethyl benzoic acid (3AZ, green) bound to human class I MHC HLA‐A2, shown in ribbon representation (PDB ID 3o3e) . Atom color coding: C‐green or grey; N‐blue; O‐red…”