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Structure of MurF from Streptococcus pneumoniae co-crystallized with a small molecule inhibitor exhibits interdomain closure

¹ Advanced Technology and ² Metabolic Disease Research, Abbott Laboratories, Global Pharmaceutical Research & Development, Abbott Park, Illinois 60064, USA

(RECEIVED May 26, 2005; FINAL REVISION September 23, 2005; ACCEPTED September 26, 2005)

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.

Keywords: MurF; murein enzymes; peptidoglycan; multidomain structure; protein–ligand interaction; X-ray; NMR

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051604805.

Reprint requests to: Kenton L. Longenecker, Department of Structural Biology, R46Y, Building AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA; e-mail: Kenton.Longenecker{at}Abbott.com; fax: (847) 937-2625.

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