Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association.
Angew Chem Int Ed Engl
; 54(52): 15892-6, 2015 Dec 21.
Article
em En
| MEDLINE
| ID: mdl-26566002
ABSTRACT
Caseinolytic proteaseâ
P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S.â
aureus ClpP revealed a novel binding mode Because of the rotation of the conserved residue prolineâ
125, ClpP is locked in a defined conformational state, which results in distortion of the catalytic triad and inhibition of the peptidase activity. Based on these structural insights, the molecule was optimized by rational design and virtual screening, resulting in derivatives exceeding the potency of previous ClpP inhibitors. Strikingly, the conformational lock is overturned by binding of ClpX, an associated chaperone that enables proteolysis by substrate unfolding in the ClpXP complex. Thus, regulation of inhibitor binding by associated chaperones is an unexpected mechanism important for ClpP drug development.
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Base de dados:
MEDLINE
Assunto principal:
Serina Endopeptidases
/
Inibidores de Serina Proteinase
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article