Inhibition of protein synthesis under the magnifying glass
Visualization of inhibitors binding sites on the two subunits of the eukaryotic ribosome. There are four main binding sites: the binding area of the messenger RNA, the decoding center, the E-site binding site of transfer RNA and the peptidyl transferase center.
Nature Sept. 25, 2014
Sept. 10, 2014
Protein biosynthesis is an essential for biological process that takes place in all living cells and is performed by the ribosomes. Understanding the highly complex structure of the ribosomes and their blocking agents is a challenge that have tried to meet for several years the teams of Marat Yusupov and Gulnara Yusupova at IGBMC. In their latest work published on September 10th in Nature, they reveal the high resolution structures of the eukaryotic ribosome, in complex with no less than 16 inhibitors, providing critical new data for the development of new drugs.
Ribosomes in question
Cornerstones of protein translation and therefore expression of genes, ribosomes are vital for cells. Mastering these complexes to better inhibit them is a secret that wish to drill a large number of researchers, so great is its therapeutic potential. Today, for example, half of known antibiotics target the bacterial ribosome. Controlling the inhibition of ribosomes in general would open a new significant field of applications, ranging from infections to cancer through genetic diseases.
A catalog of inhibitors
Here the researchers were interested in the eukaryotic (non-bacterial) ribosome, very different from its bacterial counterpart, and more specifically in the yeast ribosome. After determining its structure with more and more precision in 2010 and 2011, researchers managed to crystallize it in complex with various inhibitors and thereby determine with surprising accuracy the structural characteristics of each binding domain. Their latest study published in Nature offers a structural catalog of 16 inhibitors in complex with the ribosome, thereby providing for the first time crucial data on atomic level for the development of specific drugs.
An action localized in time and space
By locating with pinpoint accuracy the binding domains of each inhibitor on the ribosome, the researchers were able to shed light on their different bonding sites and mechanisms of action during the translation cycle. Kinetic studies also allowed them to observe that two inhibitors of the same family are surprisingly not acting exactly at the same time of the translation, a difference that may be explained by their difference in size. Indeed, while the smallest inhibitor can quickly access the ribosome, the larger one struggles to attain the very complex machinery of the ribosome and binds to it only during the initial stages of translation. If confirmed with other inhibitors, this hypothesis provides an important new data to facilitate future drug development.
What about resistance?
Mechanisms of antibiotic resistance result from the natural selection that allows bacteria to adapt. While the ribosome is composed of ribosomal RNA and proteins, mutations in the bacterial ribosome affect both rRNA and proteins, providing a wide range of possible resistances. However in the case of the eukaryotic ribosome, as rRNA are encoded by several hundred genes, mutations are rare at this level, affecting mainly proteins. These new data suggest that the eukaryotic ribosome is less sensitive to the phenomenon of resistance and that targeting the inhibitors whose binding domains are mainly composed of rRNA, would limit the possibilities for the emergence of resistance.
The author of this study, Nicolas Garreau of Loubresse, together with Marat Yusupov, Gulnara Yusupova and Jean-Paul Renaud, are carrying the Ribostruct project for the development of a start-up that will offer an approach for the rational and optimized development of ribosome-inhibiting drugs. Nicolas recently won the national competition for the creation of innovative start-up companies in the “emergence” category and received a technology maturation support for innovative projects from SATT Conectus Alsace.
In general, this study reveals for the first time the modes of action of several specific inhibitory molecules of the eukaryotic ribosome on atomic level, and suggests the future development of drugs targeting these mechanisms for customized treatment of certain infectious diseases, cancers and genetic diseases.