Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes

Agnieszka Lewandowska; Corinne P. Soutar; Alexander I. Greenwood; Evgeny Nimerovsky; Ashley M. De Lio; Jordan T. Holler; Grant S. Hisao; Anuj Khandelwal; Jiabao Zhang; Anna M. SantaMaria; Charles D. Schwieters; Taras V. Pogorelov; Martin Burke; Chad Rienstra

doi:10.1038/s41594-021-00685-4

Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes

Agnieszka Lewandowska, Corinne P. Soutar, Alexander I. Greenwood, Evgeny Nimerovsky, Ashley M. De Lio, Jordan T. Holler, Grant S. Hisao, Anuj Khandelwal, Jiabao Zhang, Anna M. SantaMaria, Charles D. Schwieters, Taras V. Pogorelov, Martin Burke, Chad Rienstra

Research output: Contribution to journal › Article › peer-review

Abstract

Amphotericin B (AmB) is a powerful but toxic fungicide that operates via enigmatic small molecule–small molecule interactions. This mechanism has challenged the frontiers of structural biology for half a century. We recently showed AmB primarily forms extramembranous aggregates that kill yeast by extracting ergosterol from membranes. Here, we report key structural features of these antifungal ‘sponges’ illuminated by high-resolution magic-angle spinning solid-state NMR, in concert with simulated annealing and molecular dynamics computations. The minimal unit of assembly is an asymmetric head-to-tail homodimer: one molecule adopts an all-trans C1–C13 motif, the other a C6–C7-gauche conformation. These homodimers are staggered in a clathrate-like lattice with large void volumes similar to the size of sterols. These results illuminate the atomistic interactions that underlie fungicidal assemblies of AmB and suggest this natural product may form biologically active clathrates that host sterol guests.

Original language	English (US)
Pages (from-to)	972-981
Number of pages	10
Journal	Nature Structural Biology
Volume	28
Issue number	12
DOIs	https://doi.org/10.1038/s41594-021-00685-4
State	Published - Dec 2021

Keywords

Drug discovery
Supramolecular assembly
Solid-state NMR

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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Lewandowska, A., Soutar, C. P., Greenwood, A. I., Nimerovsky, E., De Lio, A. M., Holler, J. T., Hisao, G. S., Khandelwal, A., Zhang, J., SantaMaria, A. M., Schwieters, C. D., Pogorelov, T. V., Burke, M., & Rienstra, C. (2021). Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes. Nature Structural Biology, 28(12), 972-981. https://doi.org/10.1038/s41594-021-00685-4

Lewandowska, A, Soutar, CP, Greenwood, AI, Nimerovsky, E, De Lio, AM, Holler, JT, Hisao, GS, Khandelwal, A, Zhang, J, SantaMaria, AM, Schwieters, CD, Pogorelov, TV , Burke, M & Rienstra, C 2021, 'Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes', Nature Structural Biology, vol. 28, no. 12, pp. 972-981. https://doi.org/10.1038/s41594-021-00685-4

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title = "Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes",

abstract = "Amphotericin B (AmB) is a powerful but toxic fungicide that operates via enigmatic small molecule–small molecule interactions. This mechanism has challenged the frontiers of structural biology for half a century. We recently showed AmB primarily forms extramembranous aggregates that kill yeast by extracting ergosterol from membranes. Here, we report key structural features of these antifungal {\textquoteleft}sponges{\textquoteright} illuminated by high-resolution magic-angle spinning solid-state NMR, in concert with simulated annealing and molecular dynamics computations. The minimal unit of assembly is an asymmetric head-to-tail homodimer: one molecule adopts an all-trans C1–C13 motif, the other a C6–C7-gauche conformation. These homodimers are staggered in a clathrate-like lattice with large void volumes similar to the size of sterols. These results illuminate the atomistic interactions that underlie fungicidal assemblies of AmB and suggest this natural product may form biologically active clathrates that host sterol guests.",

keywords = "Drug discovery, Supramolecular assembly, Solid-state NMR",

author = "Agnieszka Lewandowska and Soutar, {Corinne P.} and Greenwood, {Alexander I.} and Evgeny Nimerovsky and {De Lio}, {Ashley M.} and Holler, {Jordan T.} and Hisao, {Grant S.} and Anuj Khandelwal and Jiabao Zhang and SantaMaria, {Anna M.} and Schwieters, {Charles D.} and Pogorelov, {Taras V.} and Martin Burke and Chad Rienstra",

note = "Funding Information: This work was supported by the US National Institutes of Health (NIH) R01-GM112845 and R01-GM123455 to C.M.R. and R35-GM118185 to M.D.B. This study made use of the National Magnetic Resonance Facility at Madison, including the technology development program which is supported by NIH grant P41GM136463. C.D.S. was supported by the National Institutes of Health Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. We would like to dedicate this paper to the memory of our coauthor, A. Khandelwal, who passed away during the course of this investigation. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = dec,

doi = "10.1038/s41594-021-00685-4",

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AU - Lewandowska, Agnieszka

AU - Soutar, Corinne P.

AU - Greenwood, Alexander I.

AU - Nimerovsky, Evgeny

AU - De Lio, Ashley M.

AU - Holler, Jordan T.

AU - Hisao, Grant S.

AU - Khandelwal, Anuj

AU - Zhang, Jiabao

AU - SantaMaria, Anna M.

AU - Schwieters, Charles D.

AU - Pogorelov, Taras V.

AU - Burke, Martin

AU - Rienstra, Chad

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PY - 2021/12

Y1 - 2021/12

N2 - Amphotericin B (AmB) is a powerful but toxic fungicide that operates via enigmatic small molecule–small molecule interactions. This mechanism has challenged the frontiers of structural biology for half a century. We recently showed AmB primarily forms extramembranous aggregates that kill yeast by extracting ergosterol from membranes. Here, we report key structural features of these antifungal ‘sponges’ illuminated by high-resolution magic-angle spinning solid-state NMR, in concert with simulated annealing and molecular dynamics computations. The minimal unit of assembly is an asymmetric head-to-tail homodimer: one molecule adopts an all-trans C1–C13 motif, the other a C6–C7-gauche conformation. These homodimers are staggered in a clathrate-like lattice with large void volumes similar to the size of sterols. These results illuminate the atomistic interactions that underlie fungicidal assemblies of AmB and suggest this natural product may form biologically active clathrates that host sterol guests.

AB - Amphotericin B (AmB) is a powerful but toxic fungicide that operates via enigmatic small molecule–small molecule interactions. This mechanism has challenged the frontiers of structural biology for half a century. We recently showed AmB primarily forms extramembranous aggregates that kill yeast by extracting ergosterol from membranes. Here, we report key structural features of these antifungal ‘sponges’ illuminated by high-resolution magic-angle spinning solid-state NMR, in concert with simulated annealing and molecular dynamics computations. The minimal unit of assembly is an asymmetric head-to-tail homodimer: one molecule adopts an all-trans C1–C13 motif, the other a C6–C7-gauche conformation. These homodimers are staggered in a clathrate-like lattice with large void volumes similar to the size of sterols. These results illuminate the atomistic interactions that underlie fungicidal assemblies of AmB and suggest this natural product may form biologically active clathrates that host sterol guests.

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KW - Solid-state NMR

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JO - Nature Structural Biology

JF - Nature Structural Biology

IS - 12

ER -

Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes

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