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Titolo:
Bifunctional inhibitors of the trypsin-like activity of eukaryotic proteasomes
Autore:
Loidl, G; Groll, M; Musiol, HJ; Ditzel, L; Huber, R; Moroder, L;
Indirizzi:
Max Planck Inst Biochem, D-82152 Martinsried, Germany Max Planck Inst Biochem Martinsried Germany D-82152 Martinsried, Germany
Titolo Testata:
CHEMISTRY & BIOLOGY
fascicolo: 4, volume: 6, anno: 1999,
pagine: 197 - 204
SICI:
1074-5521(199904)6:4<197:BIOTTA>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
YEAST 20S PROTEASOME; MULTICATALYTIC PROTEINASE COMPLEX; CATALYTIC PROPERTIES; BETA-LACTONE; LACTACYSTIN; DEGRADATION; SUBUNITS; IDENTIFICATION; ACIDOPHILUM; RESOLUTION;
Keywords:
eukaryotic proteasome; selective inhibition; trypsin-like activity; X-ray analysis;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Moroder, L Max Planck Inst Biochem, D-82152 Martinsried, Germany Max Planck Inst Biochem Martinsried Germany D-82152 , Germany
Citazione:
G. Loidl et al., "Bifunctional inhibitors of the trypsin-like activity of eukaryotic proteasomes", CHEM BIOL, 6(4), 1999, pp. 197-204

Abstract

Background: The 20S proteasome is a multicatalytic protease complex that exhibits trypsin-like, chymotrypsin-like and post-glutamyl-peptide hydrolytic activities associated with the active sites of the beta 2, beta 5 and pr subunits, respectively. Modulation of these activities using inhibitors is essential for a better understanding of the proteasome's mechanism of action. Although there are highly selective inhibitors of the proteasome's chymotryptic activity, inhibitors of similar specificity have not yet been identified for the other activities. Results: The X-ray structure of the yeast proteasome reveals that the sidechain of Cys118 of the beta 3 subunit protrudes into the S3 subsite of the beta 2 active site. The location of this residue was exploited for the rational design of bidentated inhibitors containing a maleinimide moiety at theP3 position for covalent linkage to the thiol group and a carboxy-terminalaldehyde group for hemiacetal formation with the Thr1 hydroxyl group of the active site. Structure-based modelling was used to determine the optimal spacing of the maleinimide group from the P2-P1 dipeptide aldehydes and thespecificity of the S1 subsite was exploited to limit the inhibitory activity to the beta 2 active site. X-ray crystallographic analysis of a yeast proteasome-inhibitor adduct confirmed the expected irreversible binding of the inhibitor to the P3 subsite. Conclusions: Maleoyl-beta-alanyl-valyl-arginal is a new type of inhibitor that is highly selective for the trypsin-like activity of eukaryotic proteasomes. Despite the reactivity of the maleinimide group towards thiols, and therefore the limited use of this inhibitor for in vitro studies, it might represent an interesting new biochemical tool.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 21:42:38