Self-assembly, stability and conductance of amphotericin B channels: bridging the gap between structure and function

Zielińska, Joanna; Wieczór, Miłosz; Chodnicki, Paweł; Grela, Ewa; Luchowski, Rafał; Nierzwicki, Łukasz; Bączek, Tomasz; Gruszecki, Wiesław I.

doi:10.1039/d0nr07707k

Cited by 16 publications

(20 citation statements)

References 48 publications

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“…1B/C, and Fig. S12), even though the single length assembly was assumed to be too short to function as an ion channel (14). We also found that intermolecular hydrogen bonds from the amino sugar moieties in AmB-AmB and AmB-Erg provide an important force that stabilizes these ion channels in an active form (Fig.…”

Section: Discussionmentioning

confidence: 78%

Amphotericin B Assembles into Seven-Molecule Ion Channels: An NMR and Molecular Dynamics Study

Umegawa

Yamamoto²,

Dixit

et al. 2021

Preprint

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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 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 high-resolution 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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Section: Discussionmentioning

confidence: 78%

Amphotericin B Assembles into Seven-Molecule Ion Channels: An NMR and Molecular Dynamics Study

Umegawa

Yamamoto²,

Dixit

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The average number of AmB molecules per channel assembly is crucial information for determining the three-dimensional (3D) structure of the AmB channel. In the past, this number has often been estimated by channel conductance measurements ( 16 , 17 ) and MD calculations ( 18 ), but the results have been quite widely distributed from 4 to over 10. Fluorine-labeled AmB ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Amphotericin B assembles into seven-molecule ion channels: An NMR and molecular dynamics study

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

“…The average number of AmB molecules per channel assembly is crucial information for determining the 3D structure of AmB channels. Previously, this number has been estimated via channel conductance measurements 12,13 and MD calculations 14 , but the results have varied widely from four to more than ten. Fluorine-labelled AmB (Fig.…”

Section: The Number Of Amb Molecules Constituting One Channel Assemblymentioning

confidence: 99%

Amphotericin B Assembles into Seven-Molecule Ion Channels in Membrane Domain

Umegawa

Yamamoto²,

Dixit

et al. 2021

Preprint

View full text Add to dashboard Cite

Amphotericin B, a long-used antifungal drug, 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 of seven drug molecules was observed to form an ion conductive channel. The structure somewhat resembled the upper half of the barrel-stave model proposed in the 1970s but different substantially in the number of molecules and their arrangement. Based on the structure obtained, the aggregation of the channel assemblies in membranes was investigated and a mechanism was proposed in which complexation with ergosterol stabilizes the drug’s assemblies, leading to their aggregation, and in turn enhancing channel activity. The high-resolution structure is consistent with many previous findings, including structure-activity relationships of the drug, and the channel aggregation provides a more reasonable explanation for the selective toxicity of this drug to fungi.

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Self-assembly, stability and conductance of amphotericin B channels: bridging the gap between structure and function

Abstract: Amphotericin B (AmB), one of the most powerful but also toxic drugs used to treat systemic mycoses, is believed to selectively permeabilize fungal cell membranes to ions in a sterol-dependent manner.

Cited by 16 publications

References 48 publications

Amphotericin B Assembles into Seven-Molecule Ion Channels: An NMR and Molecular Dynamics Study

Amphotericin B Assembles into Seven-Molecule Ion Channels: An NMR and Molecular Dynamics Study

Amphotericin B assembles into seven-molecule ion channels: An NMR and molecular dynamics study

Amphotericin B Assembles into Seven-Molecule Ion Channels in Membrane Domain

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