Journal article
A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface
Proceedings of the National Academy of Sciences - PNAS, v 106(33), pp 13759-13764
18 Aug 2009
PMID: 19666597
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The glycodepsipeptide antibiotic ramoplanin A2 is in late stage clinical development for the treatment of infections from Gram-positive pathogens, especially those that are resistant to first line antibiotics such as vancomycin. Ramoplanin A2 achieves its antibacterial effects by interfering with production of the bacterial cell wall; it indirectly inhibits the transglycosylases responsible for peptidoglycan biosynthesis by sequestering their Lipid II substrate. Lipid II recognition and sequestration occur at the interface between the extracellular environment and the bacterial membrane. Therefore, we determined the structure of ramoplanin A2 in an amphipathic environment, using detergents as membrane mimetics, to provide the most physiologically relevant structural context for mechanistic and pharmacological studies. We report here the X-ray crystal structure of ramoplanin A2 at a resolution of 1.4 Å. This structure reveals that ramoplanin A2 forms an intimate and highly amphipathic dimer and illustrates the potential means by which it interacts with bacterial target membranes. The structure also suggests a mechanism by which ramoplanin A2 recognizes its Lipid II ligand.
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Details
- Title
- A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface
- Creators
- James B Hamburger - Department of Chemistry, Duke University, Durham, NC 27708; andAmanda J Hoertz - Department of Chemistry, Duke University, Durham, NC 27708; andAmy Lee - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19129Rachel J Senturia - Department of Chemistry, Duke University, Durham, NC 27708; andDewey G McCafferty - Department of Chemistry, Duke University, Durham, NC 27708; andPatrick J Loll - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19129
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 106(33), pp 13759-13764
- Publisher
- National Academy of Sciences
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000269078700026
- Scopus ID
- 2-s2.0-69549113356
- Other Identifier
- 991014877805504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology