Solution Structure of Polytheonamide B, a Highly Cytotoxic Nonribosomal Polypeptide from Marine Sponge

Polytheonamide B (pTB), a highly cytotoxic polypeptide, is one of the most unusual nonribosomal peptides of sponge origin. pTB is a linear 48-residue peptide with alternating d- and l-amino acids and contains a total of eight types of nonproteinogenic amino acids. To investigate the mechanisms under...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2010-09, Vol.132 (37), p.12941-12945
Main Authors: Hamada, Toshiyuki, Matsunaga, Shigeki, Fujiwara, Masako, Fujita, Kenichi, Hirota, Hiroshi, Schmucki, Roland, Güntert, Peter, Fusetani, Nobuhiro
Format: Article
Language:English
Subjects:
Animals
Biomimetics
Cell Line, Tumor
Cell Membrane - metabolism
Inhibitory Concentration 50
Ion Channels - metabolism
Mice
Models, Molecular
Nuclear Magnetic Resonance, Biomolecular
Organic Chemicals - chemistry
Peptides - chemistry
Peptides - metabolism
Peptides - pharmacology
Porifera - chemistry
Protein Conformation
Proteins - chemistry
Proteins - metabolism
Proteins - pharmacology
Solutions
Solvents - chemistry
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Summary:Polytheonamide B (pTB), a highly cytotoxic polypeptide, is one of the most unusual nonribosomal peptides of sponge origin. pTB is a linear 48-residue peptide with alternating d- and l-amino acids and contains a total of eight types of nonproteinogenic amino acids. To investigate the mechanisms underlying its cytotoxic activity, we determined the three-dimensional structure of pTB by NMR spectroscopy, structure calculation, and energy minimization. pTB adopts a single right-handed β6.3-helical structure in a 1:1 mixture of methanol/chloroform with a length of approximately 45 Å and a hydrophilic pore of ca. 4 Å inner diameter. These features indicate that pTB molecules form transmembrane channels that permeate monovalent cations as gramicidin A channels do. The strong cytotoxicity of pTB can be ascribed to its ability to form single molecule channels through biological membranes.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja104616z