Structure of MurF from Streptococcus pneumoniae co-crystallized with a small molecule inhibitor exhibits interdomain closure.
Protein Sci
; 14(12): 3039-47, 2005 Dec.
Article
en En
| MEDLINE
| ID: mdl-16322581
ABSTRACT
In a broad genomics analysis to find novel protein targets for antibiotic discovery, MurF was identified as an essential gene product for Streptococcus pneumonia that catalyzes a critical reaction in the biosynthesis of the peptidoglycan in the formation of the cell wall. Lacking close relatives in mammalian biology, MurF presents attractive characteristics as a potential drug target. Initial screening of the Abbott small-molecule compound collection identified several compounds for further validation as pharmaceutical leads. Here we report the integrated efforts of NMR and X-ray crystallography, which reveal the multidomain structure of a MurF-inhibitor complex in a compact conformation that differs dramatically from related structures. The lead molecule is bound in the substrate-binding region and induces domain closure, suggestive of the domain arrangement for the as yet unobserved transition state conformation for MurF enzymes. The results form a basis for directed optimization of the compound lead by structure-based design to explore the suitability of MurF as a pharmaceutical target.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Péptido Sintasas
/
Streptococcus pneumoniae
/
Inhibidores Enzimáticos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2005
Tipo del documento:
Article