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M109098200v1
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Papers In Press, published online ahead of print October 15, 2001
J. Biol. Chem, 10.1074/jbc.M109098200
Submitted on September 20, 2001
Revised on October 10, 2001
Accepted on October 15, 2001

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

Kirsten Falk, Julie Lau, Laura Santambrogio, Viviana Marin Esteban, Fabiola Puentes, Jack L. Strominger, and Olaf Rötzschke

Cellular Immunology of Autoimmune Reactions, Max-Delbrück-Center of Molecular Medicine (MDC), Berlin D-13125

Corresponding Author: roetzsch{at}mdc-berlin.de

Hydrogen bonds (H-bonds) are crucial for the stability of the peptide/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 catalyse 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 APC 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.


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