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Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity
- Source :
- Cell
- Publication Year :
- 2012
-
Abstract
- Constitutive proteasomes and immunoproteasomes shape the peptide repertoire presented by major histocompatibility complex class I (MHC-I) molecules by harboring different sets of catalytically active subunits. Here, we present the crystal structures of constitutive proteasomes and immunoproteasomes from mouse in the presence and absence of the epoxyketone inhibitor PR-957 (ONX 0914) at 2.9 Å resolution. Based on our X-ray data, we propose a unique catalytic feature for the immunoproteasome subunit Beta5i/LMP7. Comparison of ligand-free and ligand-bound proteasomes reveals conformational changes in the S1 pocket of Beta5c/X but not Beta5i, thereby explaining the selectivity of PR-957 for Beta5i. Time-resolved structures of yeast proteasome: PR-957 complexes indicate that ligand docking to the active site occurs only via the reactive head group and the P1 side chain. Together, our results support structure-guided design of inhibitory lead structures selective for immunoproteasomes that are linked to cytokine production and diseases like cancer and autoimmune disorders.
- Subjects :
- Models, Molecular
Proteasome Endopeptidase Complex
Protein subunit
Molecular Sequence Data
Peptide
Saccharomyces cerevisiae
Crystallography, X-Ray
Major histocompatibility complex
General Biochemistry, Genetics and Molecular Biology
Mice
03 medical and health sciences
0302 clinical medicine
ddc:570
Hydrolase
Animals
Amino Acid Sequence
030304 developmental biology
chemistry.chemical_classification
Antigen Presentation
0303 health sciences
biology
Biochemistry, Genetics and Molecular Biology(all)
Histocompatibility Antigens Class I
Active site
Yeast
3. Good health
Cell biology
Proteasome
Biochemistry
chemistry
Docking (molecular)
030220 oncology & carcinogenesis
biology.protein
Oligopeptides
Proteasome Inhibitors
Sequence Alignment
Subjects
Details
- Volume :
- 148
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Cell
- Accession number :
- edsair.doi.dedup.....8fcdb3ecade98eaf384181ea58bd1db5