2am2: Difference between revisions

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.

[[Category: Bartley, D M.]]

[[Category: Fry, E H.]]

[[Category: Hajduk, P J.]]

[[Category: Harlan, J E.]]

[[Category: Jakob, C G.]]

[[Category: Longenecker, K L.]]

[[Category: Solomon, L R.]]

[[Category: Stamper, G F.]]

[[Category: Walter, K A.]]

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