Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity.
Cell
; 148(4): 727-38, 2012 Feb 17.
Article
em En
| MEDLINE
| ID: mdl-22341445
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 ß5i/LMP7. Comparison of ligand-free and ligand-bound proteasomes reveals conformational changes in the S1 pocket of ß5c/X but not ß5i, thereby explaining the selectivity of PR-957 for ß5i. Time-resolved structures of yeast proteasomePR-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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Saccharomyces cerevisiae
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Cristalografia por Raios X
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Complexo de Endopeptidases do Proteassoma
Limite:
Animals
Idioma:
En
Revista:
Cell
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Alemanha