The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth

Simple item page
dc.contributor.authorPellegrino, Simone
dc.contributor.authorMeyer, Melanie
dc.contributor.authorZorbas, Christiane
dc.contributor.authorBouchta, Soumaya A.
dc.contributor.authorSaraf, Kritika
dc.contributor.authorPelly, Stephen C.
dc.contributor.authorYusupova, Gulnara
dc.contributor.authorEvidente, Antonio
dc.contributor.authorMathieu, Veronique
dc.contributor.authorKornienko, Alexander
dc.contributor.authorLafontaine, Denis
dc.contributor.authorYusupov, Marat
dc.date.accessioned2019-12-17T17:44:19Z
dc.date.available2019-12-17T17:44:19Z
dc.date.issued2018-03
dc.description.abstractAlkaloids isolated from the Amaryllidaceae plants have potential as therapeutics for treating human diseases. Haemanthamine has been studied as a novel anticancer agent due to its ability to overcome cancer cell resistance to apoptosis. Biochemical experiments have suggested that hemanthamine targets the ribosome. However, a structural characterization of its mechanism has been missing. Here we present the 3.1 Å resolution X-ray structure of haemanthamine bound to the Saccharomyces cerevisiae 80S ribosome. This structure reveals that haemanthamine targets the A-site cleft on the large ribosomal subunit rearranging rRNA to halt the elongation phase of translation. Furthermore, we provide evidence that haemanthamine and other Amaryllidaceae alkaloids also inhibit specifically ribosome biogenesis, triggering nucleolar stress response and leading to p53 stabilization in cancer cells. Together with a computer-aided interpretation of existing structure-activity relationships of Amaryllidaceae alkaloids congeners, we provide a rationale for designing molecules with enhanced potencies and reduced toxicities.
dc.description.departmentChemistry and Biochemistry
dc.description.versionThis is the accepted manuscript version of an article published in Structure.
dc.formatText
dc.format.extent15 pages
dc.format.medium1 file (.pdf)
dc.identifier.citationPellegrino, S., Meyer, M., Zorbas, C., Bouchta, S. A., Saraf, K., Pelly, S. C., Yusupova, G., Evidente, A., Mathieu, V., Komienko, A., Lafontaine, D. L. J., Yusupov, M. (2018). The Amaryllidaceae Alkaloid Haemanthamine binds the eukaryotic ribosome to repress cancer cell growth. Structure, 26(3), pp. 416–425.
dc.identifier.doihttps://doi.org/10.1016/j.str.2018.01.009
dc.identifier.issn1878-4186
dc.identifier.urihttps://hdl.handle.net/10877/9095
dc.language.isoen
dc.publisherElsevier
dc.sourceStructure, 2018, Vol. 26, No. 3, pp. 416–425.
dc.subjectx-ray crystallography
dc.subjectcancer
dc.subjecthaemanthamine
dc.subjectnucleolar stress response
dc.subjectp53
dc.subjectpeptidyl transferase center
dc.subjectribosome
dc.subjectribosome biogenesis
dc.subjecttranslation elongation
dc.subjectAmaryllidaceae alkaloids
dc.subjectChemistry and Biochemistry
dc.titleThe Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth
dc.typeArticle

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
Structure.pdf
Size:
1.86 MB
Format:
Adobe Portable Document Format
Description:
Download

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
2.54 KB
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

College of Science and Engineering