Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors.
Sci Adv
; 5(9): eaaw3818, 2019 09.
Article
en En
| MEDLINE
| ID: mdl-31517045
ABSTRACT
Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic bacteria. Activation of different ClpPs by inhibitors has been independently reported from drug development efforts, but no rationale for inhibitor-induced activation has been hitherto proposed. Using an integrated approach that includes x-ray crystallography, solid- and solution-state nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the proteasome inhibitor bortezomib binds to the ClpP active-site serine, mimicking a peptide substrate, and induces a concerted allosteric activation of the complex. The bortezomib-activated conformation also exhibits a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism, where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association and protein processive degradation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores de Proteasas
/
Proteínas Bacterianas
/
Thermus thermophilus
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Endopeptidasa Clp
Idioma:
En
Revista:
Sci Adv
Año:
2019
Tipo del documento:
Article
País de afiliación:
Francia