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Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4576-9. Epub 2006 Mar 13.

Inhibitor-binding mode of homobelactosin C to proteasomes: new insights into class I MHC ligand generation.

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  • 1Ludwig Maximilians Universität, Adolf Butenandt Institut, Butenandtstrasse 5, Gebäude B, D-81377 Munich, Germany.


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-gamma 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.

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