4PV8: Crystal Structure of H2Kb-Q600F complex

Citation:
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.
PDB ID: 4PV8Download
MMDB ID: 156751
PDB Deposition Date: 2014/3/15
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 2.31  Å
Source Organism:
Mus musculus
Similar Structures:
Biological Unit for 4PV8: trimeric; determined by author and by software (PISA)
Molecular Components in 4PV8
Label Count Molecule
Proteins (3 molecules)
1
H-2 Class I Histocompatibility Antigen, K-B Alpha Chain(Gene symbol: H2-K1)
Molecule annotation
1
Beta-2-microglobulin(Gene symbol: B2m)
Molecule annotation
1
S598 Peptide Modified Q600f
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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