| Autor: |
Longenecker KL; Department of Structural Biology, R46Y, Building AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA. Kenton.Longenecker@Abbott.com, Stamper GF, Hajduk PJ, Fry EH, Jakob CG, Harlan JE, Edalji R, Bartley DM, Walter KA, Solomon LR, Holzman TF, Gu YG, Lerner CG, Beutel BA, Stoll VS |
| Jazyk: |
angličtina |
| Zdroj: |
Protein science : a publication of the Protein Society [Protein Sci] 2005 Dec; Vol. 14 (12), pp. 3039-47. |
| DOI: |
10.1110/ps.051604805 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
Plný text