期刊
JOURNAL OF IMMUNOLOGY
卷 195, 期 3, 页码 1251-1261出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1402367
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资金
- National Institute of General Medical Sciences of the National Institutes of Health [P20GM103395]
- Pfizer [WS1907326]
Peptides bind MHC class II molecules through a thermodynamically nonadditive process consequent to the flexibility of the reactants. Currently, how the specific outcome of this binding process affects the ensuing epitope selection needs resolution. Calorimetric assessment of binding thermodynamics for hemagglutinin 306-319 peptide variants to the human MHC class II HLA-DR1 (DR1) and a mutant DR1 reveals that peptide/DR1 complexes can be formed with different enthalpic and entropic contributions. Complexes formed with a smaller entropic penalty feature circular dichroism spectra consistent with a non-compact form, and molecular dynamics simulation shows a more flexible structure. The opposite binding mode, compact and less flexible, is associated with greater entropic penalty. These structural variations are associated with rearrangements of residues known to be involved in HLA-DR (DM) binding, affinity of DM for the complex, and complex susceptibility to DM-mediated peptide exchange. Thus, the thermodynamic mechanism of peptide binding to DR1 correlates with the structural rigidity of the complex, and DM mediates peptide exchange by sensing flexible complexes in which the aforementioned residues are rearranged at a higher frequency than in more rigid ones.
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