Structure-function insights reveal the human ribosome as a cancer target for antibiotics.

Alexander G Myasnikov,Isabelle Hazemann,Bruno P Klaholz,S Kundhavai Natchiar,Jean-François Peyron,Véronique Imbert,Heena Khatter,Marielle Nebout

doi:10.1038/ncomms12856

Abstract

Many antibiotics in clinical use target the bacterial ribosome by interfering with the protein synthesis machinery. However, targeting the human ribosome in the case of protein synthesis deregulations such as in highly proliferating cancer cells has not been investigated at the molecular level up to now. Here we report the structure of the human 80S ribosome with a eukaryote-specific antibiotic and show its anti-proliferative effect on several cancer cell lines. The structure provides insights into the detailed interactions in a ligand-binding pocket of the human ribosome that are required for structure-assisted drug design. Furthermore, anti-proliferative dose response in leukaemic cells and interference with synthesis of c-myc and mcl-1 short-lived protein markers reveals specificity of a series of eukaryote-specific antibiotics towards cytosolic rather than mitochondrial ribosomes, uncovering the human ribosome as a promising cancer target.

Highlights

Many antibiotics in clinical use target the bacterial ribosome by interfering with the protein synthesis machinery
The ribosome is the molecular machinery at the heart of protein synthesis, a highly regulated activity which is tightly connected with cell activation and proliferation, with many steps controlled by both proto-oncogenes and tumour suppressors
Human ribosomes were prepared as described[11], incubated with CHX to form the complex and the structure was determined by single particle cryo-electron microscopy (cryo-EM) and refined to an average resolution of 3.6 Å

Summary

Introduction

Many antibiotics in clinical use target the bacterial ribosome by interfering with the protein synthesis machinery. It should in principle be possible to differentially modulate protein synthesis activity of the human ribosome at sufficiently low ligand doses and thereby primarily target strongly proliferating cells such as cancer cells. Because of their high protein synthesis rate, cancer cells develop addictions and are expected to be highly sensitive to their inhibition, compared with normal untransformed cells. Importantly, we provide evidence for the antiproliferative activity of CHX which extends to a series of ligands exhibiting a marked specificity towards the cytosolic ribosome, establishing the human ribosome as a promising cancer target This structure and function analysis performed on the human ribosome using a variety of drug candidates provides important insights for the development of new antibiotics

Methods

Results

Conclusion