Journal Article

Tetracenomycin X inhibits translation by binding within the ribosomal exit tunnel

Lukianov, Dmitrii A., Leyn, Semen A., Polshakov, Vladimir I., Maviza, Tinashe P., Osterman, Andrei L., Skvortsov, Dmitry A., Dmitriev, Sergey E., Wilson, Daniel N., Bogdanov, Alexey A., Sergiev, Petr V., Zakalyukina, Yuliya V., Lashkevich, Kseniya A., Polikanov, Yury S., Wieland, Maximiliane, Zlamal, Jaime E., Osterman, Ilya A., Dontsova, Olga A., Beckmann, Roland, Shiriaev, Dmitrii I., Cheng, Jingdong, Biryukov, Mikhail V., Buschauer, Robert, Komarova, Ekaterina S., Tashlitsky, Vadim N.

2020

Overview

The increase in multi-drug resistant pathogenic bacteria is making our current arsenal of clinically used antibiotics obsolete, highlighting the urgent need for new lead compounds with distinct target binding sites to avoid cross-resistance. Here we report that the aromatic polyketide antibiotic tetracenomycin (TcmX) is a potent inhibitor of protein synthesis, and does not induce DNA damage as previously thought. Despite the structural similarity to the well-known translation inhibitor tetracycline, we show that TcmX does not interact with the small ribosomal subunit, but rather binds to the large subunit, within the polypeptide exit tunnel. This previously unappreciated binding site is located adjacent to the macrolide-binding site, where TcmX stacks on the noncanonical basepair formed by U1782 and U2586 of the 23S ribosomal RNA. Although the binding site is distinct from the macrolide antibiotics, our results indicate that like macrolides, TcmX allows translation of short oligopeptides before further translation is blocked. Structural and biochemical analysis reveal that tetracenomycin X acts as an inhibitor of protein synthesis by binding within the exit tunnel in a large ribosomal unit to prevent the prolongation of the nascent polypeptide chain.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/337/574 / 631/535/1266 / 631/92/349 / 631/92/555 / 631/92/609 / Amycolatopsis - drug effects / Amycolatopsis - genetics / Amycolatopsis - metabolism / Antibiotics / Binding Sites / Biochemical analysis / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Cross-resistance / Cryoelectron Microscopy / Deoxyribonucleic acid / DNA / DNA damage / Drug resistance / Drug Resistance, Bacterial / Escherichia coli / Gene Expression Regulation, Bacterial - drug effects / HEK293 Cells / Humans / Inhibitors / Lead compounds / Macrolide antibiotics / Microbial Sensitivity Tests / Models, Molecular / Multidrug resistance / Mutation / Naphthacenes - chemistry / Naphthacenes - pharmacology / Oligopeptides / Polypeptides / Prolongation / Protein Binding / Protein biosynthesis / Protein Biosynthesis - drug effects / Protein Conformation / Protein synthesis / Proteins / Ribosomes - metabolism / rRNA / rRNA 23S / Translation