Journal
SCIENCE ADVANCES
Volume 8, Issue 24, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abo2658
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Funding
- JSPS KAKENHI [17H06406, 16H06315]
- JST ERATO Lipid active structure project [JPMJER1005]
- Grants-in-Aid for Scientific Research [16H06315] Funding Source: KAKEN
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In this study, the three-dimensional structure of the molecular assemblies formed by Amphotericin B in membranes was experimentally elucidated using spectroscopy and simulations. The observed structure explains the drug's structure-activity relationships and will contribute to improving drug efficacy and reducing adverse effects.
Amphotericin B, an antifungal drug with a long history of use, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of the fungal sterol ergosterol. A stable assembly consisting of seven drug molecules was observed to form an ion conductive channel. The structure is somewhat similar to the upper half of the barrel-stave model proposed in the 1970s but substantially different in the number of molecules and in their arrangement. The present structure explains many previous findings, including structure-activity relationships of the drug, which will be useful for improving drug efficacy and reducing adverse effects.
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