5ON6

Crystal structure of haemanthamine bound to the 80S ribosome

This is a non-PDB format compatible entry.

Summary for 5ON6

• Entry DOI: 10.2210/pdb5on6/pdb
• Descriptor: 25S ribosomal RNA, 60S ribosomal protein L8-A, 60S ribosomal protein L9-A, ... (88 entities in total)
• Functional Keywords: ribosome, inhibitor, cancer
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); More
• Cellular location: Cytoplasm : P17076 P05738 P41805 Q3E757 Q12690 P36105 P05748 P26784 P05740 P0CX49 P0CX82 P0CX23 Q02753 P05749 P0CX41 P04449 P04456 P05743 P0C2H6 P02406 P05747 P14120 P0C2H8 P38061 P05744 P87262 P0CX84 P05745 P49166 P0CX45 P49167 P04650 P0CX87 P0CX27 P0CX25 P39015 P14126 P05317 P32905 P33442 P25443 P05750 P0CX35 P26783 P0CX37 P26786 P0CX39 P10664 O13516 Q08745 P0CX47 P48589 P05756 P39516 Q01855 P0CX51 P02407 P0CX55 P26321 P07280 P38701 P0C0V8 P0C0W1 P0CX29 P0CX31 Q3E792 P39939 P35997 Q3E7X9 Q02326 P41057 P0CX33 P38011 P05737; Ubiquitin: Cytoplasm . 60S ribosomal protein L40-A: Cytoplasm : P0CH08; Ubiquitin: Cytoplasm . 40S ribosomal protein S31: Cytoplasm : P05759 P05759
• Total number of polymer chains: 160
• Total formula weight: 6484523.00

Authors

Pellegrino, S.,Meyer, M.,Yusupova, G.,Yusupov, M. (deposition date: 2017-08-03, release date: 2018-02-28, Last modification date: 2024-05-08)

Primary citation

Pellegrino, S.,Meyer, M.,Zorbas, C.,Bouchta, S.A.,Saraf, K.,Pelly, S.C.,Yusupova, G.,Evidente, A.,Mathieu, V.,Kornienko, A.,Lafontaine, D.L.J.,Yusupov, M.
The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth.
Structure, 26:416-425.e4, 2018

PubMed Abstract: Alkaloids 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.

PubMed: 29429877
DOI: 10.1016/j.str.2018.01.009

Experimental method

X-RAY DIFFRACTION (3.10000240787 Å)