bi9b00835_si_001.pdf (1.65 MB)
The Amphotericin B–Ergosterol Complex Spans a Lipid Bilayer as a Single-Length Assembly
journal contribution
posted on 2019-12-12, 19:03 authored by Tomoya Yamamoto, Yuichi Umegawa, Hiroshi Tsuchikawa, Shinya Hanashima, Nobuaki Matsumori, Kosuke Funahashi, Sangjae Seo, Wataru Shinoda, Michio MurataAmphotericin B (AmB) is a polyene macrolide antibiotic
clinically
used as an antifungal drug. Its preferential complexation with ergosterol
(Erg), the major sterol of fungal membranes, leads to the formation
of a barrel-stave-like ion channel across a lipid bilayer. To gain
a better understanding of the mechanism of action, the mode of lipid
bilayer spanning provides essential information. However, because
of the lack of methodologies to observe it directly, it has not been
revealed for the Erg-containing channel assembly for many years. In
this study, we disclosed that the AmB–Erg complex spans a lipid
bilayer with a single-molecule length, using solid-state nuclear magnetic
resonance (NMR) experiments. Paramagnetic relaxation enhancement by
Mn2+ residing near the surface of lipid bilayers induced
the depth-dependent decay of 13C NMR signals for individual
carbon atoms of AmB. We found that both terminal segments, the 41-COOH
group and C38–C40 methyl groups, come close to the lipid bilayer
surfaces, suggesting that the AmB–Erg complex spans a palmitoyloleoylphosphatidylcholine
(POPC) bilayer with a single-molecule length. Molecular dynamics simulation
experiments further confirmed the stabilization of the AmB–Erg
complex as a single-length spanning complex. These results provide
experimental evidence of the single-length complex incorporated in
the membrane by making thinner a POPC–Erg bilayer that mimics
fungal membranes.
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POPCErg-containing channel assemblylipid bilayerMolecular dynamics simulation experimentsbarrel-stave-like ion channel13 C NMR signals41- COOH groupmembraneAmBSingle-Length Assembly Amphotericin Bpolyene macrolide antibioticParamagnetic relaxation enhancementlipid bilayer surfacessingle-molecule length
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