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Cell Chem Biol. 2017 May 18;24(5):605-613.e5. doi: 10.1016/j.chembiol.2017.04.006. Epub 2017 Apr 27.

Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A.

Author information

1
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
2
Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, and Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
3
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U964, Illkirch 67404, France.
4
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76706, USA.
5
Department of Chemistry, Texas A&M University, College Station, TX 77842, USA.
6
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200032, China.
7
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
8
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76706, USA. Electronic address: daniel_romo@baylor.edu.
9
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104, Inserm U964, Illkirch 67404, France. Electronic address: marat@igbmc.fr.
10
Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, and Howard Hughes Medical Institute, Baltimore, MD 21205, USA. Electronic address: ragreen@jhmi.edu.
11
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address: joliu@jhu.edu.

Abstract

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.

KEYWORDS:

agelastatin A; brain cancer; chemical footprinting; drug design; marine alkaloid; molecular docking; peptidyl transferase center; rRNA seq; ribosome; translation elongation

PMID:
28457705
PMCID:
PMC5562292
DOI:
10.1016/j.chembiol.2017.04.006
[Indexed for MEDLINE]
Free PMC Article

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