4PV9

Crystal Structure of H2Kb-Q600V complex

Summary for 4PV9

• Entry DOI: 10.2210/pdb4pv9/pdb
• Related: 2ZSV 4PV8
• Descriptor: H-2 class I histocompatibility antigen, K-B alpha chain, Beta-2-microglobulin, S598 peptide modified Q600V, ... (6 entities in total)
• Functional Keywords: tcr, t cell, h2kb, heteroclitic epitopes, cd8 t cell, coronavirus, immune system
• Biological source: Mus musculus (mouse); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01901; Secreted: P01887
• Total number of polymer chains: 6
• Total formula weight: 89592.68

Authors

Twist, K.-A.,Rossjohn, J.,Gras, S. (deposition date: 2014-03-15, release date: 2014-04-23, Last modification date: 2023-12-06)

Primary citation

Trujillo, J.A.,Gras, S.,Twist, K.A.,Croft, N.P.,Channappanavar, R.,Rossjohn, J.,Purcell, A.W.,Perlman, S.
Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes.
J.Immunol., 192:5245-5256, 2014

PubMed Abstract: Peptides that bind poorly to MHC class I molecules often elicit low-functional avidity T cell responses. Peptide modification by altering the anchor residue facilitates increased binding affinity and may elicit T cells with increased functional avidity toward the native epitope ("heteroclitic"). This augmented MHC binding is likely to increase the half-life and surface density of the heteroclitic complex, but precisely how this enhanced T cell response occurs in vivo is not known. Furthermore, the ideal heteroclitic epitope will elicit T cell responses that completely cross-react with the native epitope, maximizing protection and minimizing undesirable off-target effects. Such epitopes have been difficult to identify. In this study, using mice infected with a murine coronavirus that encodes epitopes that elicit high (S510, CSLWNGPHL)- and low (S598, RCQIFANI)-functional avidity responses, we show that increased expression of peptide S598 but not S510 generated T cells with enhanced functional avidity. Thus, immune responses can be augmented toward T cell epitopes with low functional avidity by increasing Ag density. We also identified a heteroclitic epitope (RCVIFANI) that elicited a T cell response with nearly complete cross-reactivity with native epitope and demonstrated increased MHC/peptide abundance compared with native S598. Structural and thermal melt analyses indicated that the Q600V substitution enhanced stability of the peptide/MHC complex without greatly altering the antigenic surface, resulting in highly cross-reactive T cell responses. Our data highlight that increased peptide/MHC complex display contributes to heteroclitic epitope efficacy and describe parameters for maximizing immune responses that cross-react with the native epitope.

PubMed: 24795457
DOI: 10.4049/jimmunol.1400111

Experimental method

X-RAY DIFFRACTION (2 Å)