National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01 GM092218
United States
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01 CA226833
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35 GM133552
United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
K23 HL138291
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
T32 GM065086
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
T32 GM007347
United States
National Institutes of Health/National Cancer Institute (NIH/NCI)
F30 CA236131
United States
Citation
Journal: Nat Chem Biol / Year: 2022 Title: Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase. Authors: Benjamin J Reisman / Hui Guo / Haley E Ramsey / Madison T Wright / Bradley I Reinfeld / P Brent Ferrell / Gary A Sulikowski / W Kimryn Rathmell / Michael R Savona / Lars Plate / John L ...Authors: Benjamin J Reisman / Hui Guo / Haley E Ramsey / Madison T Wright / Bradley I Reinfeld / P Brent Ferrell / Gary A Sulikowski / W Kimryn Rathmell / Michael R Savona / Lars Plate / John L Rubinstein / Brian O Bachmann / Abstract: Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene- ...Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. Cryogenic electron microscopy (cryo-EM) of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence defines the mechanism of action of apoptolidin family glycomacrolides and establishes a path to address oxidative phosphorylation-dependent cancers.
History
Deposition
Apr 3, 2021
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Header (metadata) release
Aug 11, 2021
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Map release
Aug 11, 2021
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Update
May 29, 2024
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Current status
May 29, 2024
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Model: Homemade / Material: COPPER/RHODIUM / Mesh: 400 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 30 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec.
Vitrification
Cryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 4 K / Instrument: FEI VITROBOT MARK III
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Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number real images: 4019 / Average exposure time: 9.5 sec. / Average electron dose: 43.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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