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Ligand exchange of major histocompatibility complex class II proteins is triggered by H-bond donor groups of small molecules

Item Type:Article
Title:Ligand exchange of major histocompatibility complex class II proteins is triggered by H-bond donor groups of small molecules
Creators Name:Falk, K. and Lau, J.M. and Santambrogio, L. and Esteban, V.M. and Puentes, F. and Roetzschke, O. and Strominger, J.L.
Abstract:Hydrogen bonds (H-bonds) are crucial for the stability of the peptide-major histocompatibility complex (MHC) complex. In particular, the H-bonds formed between the peptide ligand and the MHC class II binding site appear to have a great influence on the half-life of the complex. Here we show that functional groups with the capacity to disrupt hydrogen bonds (e.g. -OH) can efficiently catalyze ligand exchange reactions on HLA-DR molecules. In conjunction with simple carrier molecules (such as propyl or benzyl residues), they trigger the release of low affinity ligands, which permits the rapid binding of peptides with higher affinity. Similar to HLA-DM, these compounds are able to influence the MHC class II ligand repertoire. In contrast to HLA-DM, however, these simple small molecules are still active at neutral pH. Under physiological conditions, they increase the number of "peptide-receptive" MHC class II molecules and facilitate exogenous peptide loading of dendritic cells. The drastic acceleration of the ligand exchange on these antigen presenting cells suggests that, in general, availability of H-bond donors in the extracellular milieu controls the rate of MHC class II ligand exchange reactions on the cell surface. These molecules may therefore be extremely useful for the loading of antigens onto dendritic cells for therapeutic purposes.
Keywords:1-Propanol, Antigens, Binding Sites, Cell Line, Cell Membrane, Cell Separation, Dendritic Cells, Drug Dose-Response Relationship, Enzyme-Linked Immunosorbent Assay, Epitopes, Ethanol, Fibroblasts, Flow Cytometry, HLA-D Antigens, HLA-DR Antigens, Hydrogen Bonding, Hydrogen-Ion Concentration, Ligands, Major Histocompatibility Complex, MHC Class II Genes, Peptides, Polyacrylamide Gel Electrophoresis, Protein Binding, T-Lymphocytes, Animals, Mice
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:277
Number:4
Page Range:2709-2715
Date:1 January 2002
Official Publication:https://doi.org/10.1074/jbc.M109098200
PubMed:View item in PubMed

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