Crystal structure of Staphylococcus aureus transglycosylase in complex with a lipid II analog and elucidation of peptidoglycan synthesis mechanism
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 ll-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 pyrophosphateleaving 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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2012 |
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| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:109 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huang, Chia-Ying [VerfasserIn] |
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| Links: |
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| Themen: |
Biological sciences |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
JST092563651 |
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| 100 | 1 | |a Huang, Chia-Ying |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Crystal structure of Staphylococcus aureus transglycosylase in complex with a lipid II analog and elucidation of peptidoglycan synthesis mechanism |
| 264 | 1 | |c 2012 | |
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| 520 | |a 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 ll-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 pyrophosphateleaving 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. | ||
| 540 | |a copyright © 1993-2008 National Academy of Sciences of the United States of America | ||
| 650 | 4 | |a Biological sciences |x Biochemistry |x Biomolecules |x Macromolecules |x Lipids | |
| 650 | 4 | |a Health sciences |x Medical sciences |x Pharmaceutics |x Pharmaceutical preparations |x Medications |x Antiinfectives |x Antibiotics | |
| 650 | 4 | |a Physical sciences |x Chemistry |x Chemical compounds |x Chemicals |x Polymers |x Biopolymers |x Polysaccharides | |
| 650 | 4 | |a Physical sciences |x Physics |x Condensed matter physics |x Crystallography |x Crystal morphology |x Crystal structure | |
| 650 | 4 | |a Physical sciences |x Chemistry |x Chemical compounds |x Chemicals |x Polymers |x Biopolymers |x Proteins |x Enzymes | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Genetic research |x Sequence analysis |x Sequence alignment | |
| 650 | 4 | |a Physical sciences |x Chemistry |x Chemical compounds |x Pnictogen compounds |x Phosphorus compounds |x Phosphates | |
| 650 | 4 | |a Biological sciences |x Biology |x Cytology |x Cell biology |x Cellular structures |x Cell walls | |
| 650 | 4 | |a Physical sciences |x Physics |x Fundamental forces |x Electromagnetism |x Charge density |x Electron density | |
| 650 | 4 | |a Physical sciences |x Chemistry |x Chemical compounds |x Pnictogen compounds |x Phosphorus compounds |x Phosphates |x Diphosphates | |
| 655 | 4 | |a research-article | |
| 700 | 1 | |a Shih, Hao-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Li-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Tien, Yi-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Ting-Jen Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Wei-Chieh |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Chi-Hùey |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Che |e verfasserin |4 aut | |
| 773 | 1 | 8 | |g volume:109 |g year:2012 |g number:17 |g pages:6496-6501 |
| 856 | 4 | 0 | |u https://www.jstor.org/stable/41588558 |3 Volltext |
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