title: The Structure of the Bimolecular Complex between Amphotericin B and Ergosterol in Membranes Is Stabilized by Face-to-Face van der Waals Interaction with Their Rigid Cyclic Cores.
abstract: Amphotericin B (AmB) is a polyene macrolide antibiotic isolated from Streptomyces nodosus. The antifungal activity of AmB can be attributed to the formation of an ion-channel assembly in the presence of ergosterol (Erg), in which there are two different AmB-Erg orientations, parallel and antiparallel, as reported previously. In this study, to elucidate the structures of those AmB-Erg complexes based on solid-state nuclear magnetic resonance, a (19)F-labeled AmB derivative was newly prepared by a hybrid synthesis that utilized degradation products from the drug. Using the 2-(trimethylsilyl)ethoxymethyl (SEM) group as the protecting group for the carboxylic acid moiety of AmB, the fully deprotected labeled AmB compounds were obtained successfully. Then, these labeled AmBs were subjected to (13)C{(19)F} rotational-echo double-resonance (REDOR) experiments in hydrated lipid bilayers. The results indicated the coexistence of parallel and antiparallel orientations for AmB and Erg pairing, at a ratio of 7:3. A total of six distances between AmB and Erg were successfully obtained. Geometry analysis using the distance constraints derived from the REDOR experiments provided the plausible AmB-Erg complex structure for both the parallel and antiparallel interactions. The flat macrolide of AmB and the tetracyclic core of Erg closely contacted in a face-to-face manner, thus maximizing the van der Waals interaction between the two molecules. This interaction can be attributed to the coexistence of both the parallel and antiparallel orientations.
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University , 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University , 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Umegawa
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University , 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Matsushita
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University , 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University , 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuchikawa
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University , 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hanashima
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University , 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Oishi
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University , 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Matsumori
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University , 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Murata
mesh_terms: D000666:Amphotericin B / Q000737:chemistry* / Q000378:metabolism; D000935:Antifungal Agents / Q000737:chemistry* / Q000378:metabolism; D002247:Carbon Isotopes; D002462:Cell Membrane / Q000378:metabolism*; D002942:Circular Dichroism; D004875:Ergosterol / Q000737:chemistry* / Q000378:metabolism; D005462:Fluorine Radioisotopes; D007473:Ion Channels; D008051:Lipid Bilayers / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D000072664:Provitamins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D002247:Carbon Isotopes; D005462:Fluorine Radioisotopes; D007473:Ion Channels; D008051:Lipid Bilayers; D000072664:Provitamins; D000666:Amphotericin B; D004875:Ergosterol