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

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

Research output: Contribution to journalArticle

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2709-2715
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number4
DOIs
StatePublished - Jan 25 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Falk, K., Lau, J. M., Santambrogio, L., Esteban, V. M., Puentes, F., Rötzschke, O., & Strominger, J. L. (2002). Ligand exchange of major histocompatibility complex class II proteins is triggered by H-bond donor groups of small molecules. Journal of Biological Chemistry, 277(4), 2709-2715. https://doi.org/10.1074/jbc.M109098200