Inhibitor-binding mode of homobelactosin C to proteasomes: new insights into class I MHC ligand generation.
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.
Groll
Michael
M
Ludwig Maximilians Universität, Adolf Butenandt Institut, Butenandtstrasse 5, Gebäude B, D-81377 Munich, Germany. mgroll@med.uni-muenchen.de
Larionov
Oleg V
OV
Huber
Robert
R
de Meijere
Armin
A
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D008024:Ligands; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D021122:Protein Subunits / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000201:enzymology*
D015853:Cysteine Proteinase Inhibitors; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides; D021122:Protein Subunits; C406054:belactosin C; D046988:Proteasome Endopeptidase Complex