Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A
| Autor: | Jun O. Liu, Safiat Ayinde, Rachel Green, Marat Yusupov, Brandon McClary, Junyan Lu, Mélanie Meyer, Daniel Romo, Anthony P Schuller, Boris Zinshteyn, Cheng Luo, Zufeng Guo, Gulnara Yusupova, Jeremy Chris P. Reyes, Morgan Jouanneau, Simone Pellegrino, Yongjun Dang |
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| Přispěvatelé: | Johns Hopkins University School of Medicine [Baltimore], Howard Hughes Medical Institute (HHMI), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Baylor University, Texas A&M University [College Station], Shanghai Institute of Materia Medica - Chinese Academy of Sciences [Shanghai], Fudan University [Shanghai], Yusupova, Gulnara |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
drug design Protein Conformation [SDV]Life Sciences [q-bio] Clinical Biochemistry Antineoplastic Agents Biology 01 natural sciences Biochemistry Ribosome Article 03 medical and health sciences Eukaryotic translation Alkaloids Drug Discovery Protein biosynthesis Humans Molecular Biology Oxazolidinones Pharmacology brain cancer Biological Products Dose-Response Relationship Drug 010405 organic chemistry Translation (biology) molecular docking Ribosomal RNA Footprinting 0104 chemical sciences marine alkaloid peptidyl transferase center rRNA seq translation elongation agelastatin A [SDV] Life Sciences [q-bio] Molecular Docking Simulation A-site 030104 developmental biology ribosome Protein Biosynthesis Molecular Medicine chemical footprinting Eukaryotic Ribosome Ribosomes HeLa Cells |
| Zdroj: | Cell Chemical Biology Cell Chemical Biology, 2017, 24 (5), pp.605-613.e5. ⟨10.1016/j.chembiol.2017.04.006⟩ |
| ISSN: | 2451-9448 2451-9456 |
| DOI: | 10.1016/j.chembiol.2017.04.006⟩ |
| Popis: | International audience; Protein synthesis plays an essential role in cell proliferation, differentiation, and survival. Inhibitors of eukaryotic translation have entered the clinic, establishing the translation machinery as a promising target for chemotherapy. A recently discovered, structurally unique marine sponge-derived brominated alkaloid, (-)-agelastatin A (AglA), possesses potent antitumor activity. Its underlying mechanism of action, however, has remained unknown. Using a systematic top-down approach, we show that AglA selectively inhibits protein synthesis. Using a high-throughput chemical footprinting method, we mapped the AglA-binding site to the ribosomal A site. A 3.5 Å crystal structure of the 80S eukaryotic ribosome from S. cerevisiae in complex with AglA was obtained, revealing multiple conformational changes of the nucleotide bases in the ribosome accompanying the binding of AglA. Together, these results have unraveled the mechanism of inhibition of eukaryotic translation by AglA at atomic level, paving the way for future structural modifications to develop AglA analogs into novel anticancer agents. |
| Databáze: | OpenAIRE |
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