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Crystal structure of staphylococcus aureus transglycosylase in complex with a lipid ii analog and elucidation of peptidoglycan synthesis mechanism

Academic Article
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Overview

authors

  • Huang, C. Y.
  • Shih, H. W.
  • Lin, L. Y.
  • Tien, Y. W.
  • Cheng, T. J. R.
  • Cheng, W. C.
  • Wong, Chi-Huey
  • Ma, C.

publication date

  • April 2012

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Bacterial transpeptidase and transglycosylase on the surface are essential for cell wall synthesis, and many antibiotics have been developed to target the transpeptidase; however, the problem of antibiotic resistance has arisen and caused a major threat in bacterial infection. The transglycosylase has been considered to be another excellent target, but no antibiotics have been developed to target this enzyme. Here, we determined the crystal structure of the Staphylococcus aureus membrane-bound transglycosylase, monofunctional glycosyltransferase, in complex with a lipid II analog to 2.3 Å resolution. Our results showed that the lipid II-contacting residues are not only conserved in WT and drug-resistant bacteria but also significant in enzymatic activity. Mechanistically, we proposed that K140 and R148 in the donor site, instead of the previously proposed E156, are used to stabilize the pyrophosphate-leaving group of lipid II, and E100 in the acceptor site acts as general base for the 4-OH of GlcNAc to facilitate the transglycosylation reaction. This mechanism, further supported by mutagenesis study and the structure of monofunctional glycosyltransferase in complex with moenomycin in the donor site, provides a direction for antibacterial drugs design.

subject areas

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Glycosyltransferases
  • Lipids
  • Models, Molecular
  • Molecular Sequence Data
  • Peptidoglycan
  • Protein Conformation
  • Sequence Homology, Amino Acid
  • Staphylococcus aureus
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Research

keywords

  • antibiotic discovery
  • bacterial cell wall synthesis
  • membrane protein structure
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Identity

PubMed Central ID

  • PMC3340074

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1203900109

PubMed ID

  • 22493270
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Additional Document Info

start page

  • 6496

end page

  • 6501

volume

  • 109

issue

  • 17

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