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

被引：49

作者：

Pellegrino, Simone ^{[1
]}

Meyer, Melanie ^{[1
]}

Zorbas, Christiane ^{[2
,3
,4
]}

Bouchta, Soumaya A. ^{[2
,3
,4
]}

Saraf, Kritika ^{[2
,3
,4
]}

Pelly, Stephen C. ^{[5
]}

Yusupova, Gulnara ^{[1
]}

Evidente, Antonio ^{[6
]}

Mathieu, Veronique ^{[7
]}

Kornienko, Alexander ^{[8
]}

Lafontaine, Denis L. J. ^{[2
,3
,4
]}

Yusupov, Marat ^{[1
]}

机构：

[1] Univ Strasbourg, IGBMC, CNRS UMR7104, INSERM U964, F-67404 Illkirch Graffenstaden, France

[2] Fonds Natl Rech FRS FNRS, RNA Mol Biol, BioPk Campus, B-6041 Gosselies, Belgium

[3] Fonds Natl Rech FRS FNRS, Ctr Microscopy & Mol Imaging, BioPk Campus, B-6041 Gosselies, Belgium

[4] Univ Libre Bruxelles, BioPk Campus, B-6041 Gosselies, Belgium

[5] Stellenbosch Univ, Dept Chem & Polymer Sci, ZA-7602 Stellenbosch, Matieland, South Africa

[6] Univ Napoli Federico II, Dipartimento Sci Chim, Complesso Univ Monte St Angelo,Via Cintia 4, I-80126 Naples, Italy

[7] Univ Libre Bruxelles, Lab Cancerol & Toxicol Expt, Fac Pharm, B-1050 Brussels, Belgium

[8] Texas State Univ, Dept Chem & Biochem, San Marcos, TX 78666 USA

来源：

STRUCTURE | 2018年 / 26卷 / 03期

基金：

欧洲研究理事会;

关键词：

PEPTIDYL TRANSFERASE CENTER; RNA-POLYMERASE I; PROTEIN-SYNTHESIS; STRUCTURAL BASIS; TRANSLATION; BIOGENESIS; INHIBITION; APOPTOSIS; ANTITUMOR; AGENTS;

D O I：

10.1016/j.str.2018.01.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 angstrom 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.

引用

页码：416 / +

页数：14

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