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Science 9 March 2007:
Vol. 315. no. 5817, pp. 1402 - 1405
DOI: 10.1126/science.1136611
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Reports

Structural Insight into the Transglycosylation Step of Bacterial Cell-Wall Biosynthesis

Andrew L. Lovering, Liza H. de Castro, Daniel Lim, Natalie C. J. Strynadka*

Peptidoglycan glycosyltransferases (GTs) catalyze the polymerization step of cell-wall biosynthesis, are membrane-bound, and are highly conserved across all bacteria. Long considered the "holy grail" of antibiotic research, they represent an essential and easily accessible drug target for antibiotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus. We have determined the 2.8 angstrom structure of a bifunctional cell-wall cross-linking enzyme, including its transpeptidase and GT domains, both unliganded and complexed with the substrate analog moenomycin. The peptidoglycan GTs adopt a fold distinct from those of other GT classes. The structures give insight into critical features of the catalytic mechanism and key interactions required for enzyme inhibition.

Department of Biochemistry and Molecular Biology, and Center for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, Canada.

* To whom correspondence should be addressed. E-mail: natalie{at}byron.biochem.ubc.ca

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Enzymes Without Borders: Mobilizing Substrates, Delivering Products.
F. Forneris and A. Mattevi (2008)
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Structural and Enzymatic Analysis of MshA from Corynebacterium glutamicum: SUBSTRATE-ASSISTED CATALYSIS.
M. W. Vetting, P. A. Frantom, and J. S. Blanchard (2008)
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The Monofunctional Glycosyltransferase of Escherichia coli Localizes to the Cell Division Site and Interacts with Penicillin-Binding Protein 3, FtsW, and FtsN.
A. Derouaux, B. Wolf, C. Fraipont, E. Breukink, M. Nguyen-Disteche, and M. Terrak (2008)
J. Bacteriol. 190, 1831-1834
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Domain requirement of moenomycin binding to bifunctional transglycosylases and development of high-throughput discovery of antibiotics.
T.-J. R. Cheng, M.-T. Sung, H.-Y. Liao, Y.-F. Chang, C.-W. Chen, C.-Y. Huang, L.-Y. Chou, Y.-D. Wu, Y.-H. Chen, Y.-S. E. Cheng, et al. (2008)
PNAS 105, 431-436
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Lipid Intermediates in the Biosynthesis of Bacterial Peptidoglycan.
J. van Heijenoort (2007)
Microbiol. Mol. Biol. Rev. 71, 620-635
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Analysis of Glycan Polymers Produced by Peptidoglycan Glycosyltransferases.
D. Barrett, T.-S. A. Wang, Y. Yuan, Y. Zhang, D. Kahne, and S. Walker (2007)
J. Biol. Chem. 282, 31964-31971
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Science. ISSN 0036-8075 (print), 1095-9203 (online)