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Inhibitor-Binding Mode of Homobelactosin C to Proteasomes: New Insights into Class I MHC Ligand Generation
Michael Groll, Oleg V. Larionov, Robert Huber and Armin de Meijere
Proceedings of the National Academy of Sciences of the United States of America
Vol. 103, No. 12 (Mar. 21, 2006), pp. 4576-4579
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/30048983
Page Count: 4
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Most class I MHC ligands are generated from the vast majority of cellular proteins by proteolysis within the ubiquitin-proteasome pathway and are presented on the cell surface by MHC class I molecules. Here, we present the crystallographic analysis of yeast 20S proteasome in complex with the inhibitor homobelactosin C. The structure reveals a unique inhibitor-binding mode and provides information about the composition of proteasomal primed substrate-binding sites. IFN-γ inducible substitution of proteasomal constitutive subunits by immunosubunits modulates characteristics of generated peptides, thus producing fragments with higher preference for binding to MHC class I molecules. The structural data for the proteasome:homobelactosin C complex provide an explanation for involvement of immunosubunits in antigen generation and open perspectives for rational design of ligands, inhibiting exclusively constitutive proteasomes or immunoproteasomes.
Proceedings of the National Academy of Sciences of the United States of America © 2006 National Academy of Sciences