Time-Resolved Atomistic Imaging and Statistical Analysis of Daptomycin Oligomers with and without Calcium Ions
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- Takayuki Nakamuro
- Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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- Ko Kamei
- Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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- Keyi Sun
- Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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- Jeffrey W. Bode
- Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zürich, Zürich 8093, Switzerland
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- Koji Harano
- Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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- Eiichi Nakamura
- Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
書誌事項
- 公開日
- 2022-07-20
- 資源種別
- journal article
- 権利情報
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- https://doi.org/10.15223/policy-029
- https://doi.org/10.15223/policy-037
- https://doi.org/10.15223/policy-045
- DOI
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- 10.1021/jacs.2c03949
- 10.26434/chemrxiv-2022-xdkxs
- 10.26434/chemrxiv-2022-xdkxs-v2
- 公開者
- American Chemical Society (ACS)
この論文をさがす
説明
<jats:p>Daptomycin (DP) is effective against multiple drug-resistant Gram-positive pathogens because of its distinct mechanism of action. An accepted mechanism includes Ca2+-triggered aggregation of the DP molecule to form oligomers. DP and its oligomers have so far defied structural analysis at a molecular level, and we studied the process by the combined use of dynamic light scattering in water and atomic-resolution cinematographic imaging of DP molecules captured on a carbon nanotube on which the DP molecule is installed as a fishhook. We found that the DP molecule aggregates weakly into dimers, trimers, and tetramers in water, and strongly in the presence of calcium ions, and that the tetramer is the largest oligomer in a homogeneous aqueous solution. The dimer remains as the major species under a variety of conditions, and we propose a face-to-face stacked structure based on dynamic imaging using millisecond and angstrom resolution transmission electron microscopy. The tetramer is the largest oligomer observed both in the absence and in the presence of a large excess of calcium ions. Taken together with statistical data, the microscopic structural information obtained at a single-molecule level favors a cyclic form of the dimer and the tetramer over a linear or stacked form. Such experimental structural information is new and will serve as a platform for future drug design. The data also illustrate the utility of cinematographic recording of dynamic motions of molecules for the study of self-organization processes.</jats:p>
収録刊行物
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- Journal of the American Chemical Society
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Journal of the American Chemical Society 144 (30), 13612-13622, 2022-07-20
American Chemical Society (ACS)
