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TCR‐induced alteration of primary MHC peptide anchor residue

DOI: 10.1002/eji.201948085 DOI Help

Authors: Florian Madura (Cardiff University School of Medicine) , Pierre J. Rizkallah (Cardiff University School of Medicine) , Mateusz Legut (Cardiff University School of Medicine) , Christopher J. Holland (Cardiff University School of Medicine) , Anna Fuller (Cardiff University School of Medicine) , Anna Bulek (Cardiff University School of Medicine) , Andrea J. Schauenburg (Cardiff University School of Medicine) , Andrew Trimby (Cardiff University School of Medicine) , Jade R. Hopkins (Cardiff University School of Medicine) , Stephen Wells (University of Bath) , Andrew Godkin (Cardiff University School of Medicine) , John J. Miles (Cardiff University School of Medicine; James Cook University) , Malkit Sami (Immunocore Ltd.) , Yi Li (Immunocore Ltd.) , Nathaniel Liddy (Immunocore Ltd.) , Bent K. Jakobsen (Immunocore Ltd.) , E. Joel Loveridge (Cardiff University) , David K. Cole (Cardiff University School of Medicine; Immunocore Ltd.) , Andrew K. Sewell (Cardiff University School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Immunology

State: Published (Approved)
Published: May 2019
Diamond Proposal Number(s): 4352 , 6232

Abstract: The HLA‐A*02:01‐restricted decapeptide EAAGIGILTV, derived from Melanoma Antigen Recognized by T‐cells‐1 (MART‐1) protein, represents one of the best‐studied tumor associated T‐cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptides are presented in distinct conformations by HLA‐A*02:01 and TCRs from clinically relevant T‐cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5‐HLA‐A*02:01‐AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide‐MHC anchoring. This ‘flexing’ at the TCR‐peptide‐MHC interface to accommodate the peptide antigen explains previously‐observed incongruences in this well‐studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T‐cells.

Journal Keywords: crystal structure; MART‐1/Melan‐A; peptide‐major histocompatibility complex (pMHC); surface plasmon resonance (SPR); T‐cell

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

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