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Inhibition of the Eukaryotic 80S Ribosome As a Potential Anticancer Therapy: a Structural Perspective

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Inhibition of the Eukaryotic 80S Ribosome As a Potential Anticancer Therapy: a Structural Perspective cancers Review Inhibition of the Eukaryotic 80S Ribosome as a Potential Anticancer Therapy: A Structural Perspective Simone Pellegrino 1,*,†, Salvatore Terrosu 2,†, Gulnara Yusupova 2 and Marat Yusupov 2,3,* 1 Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK 2 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France; [email protected] (S.T.); [email protected] (G.Y.) 3 Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia * Correspondence: [email protected] (S.P.); [email protected] (M.Y.) † These authors contributed equally to this work. Simple Summary: Unravelling the molecular basis of ribosomal inhibition by small molecules is crucial to characterise the function of potential anticancer drugs. After approval of the ribosome inhibitor homoharringtonine for treatment of CML, it became clear that acting on the rate of protein synthesis can be a valuable way to prevent indefinite growth of cancers. The present review discusses the state-of-the-art structural knowledge of the binding modes of inhibitors targeting the cytosolic ribosome, with the ambition of providing not only an overview of what has been achieved so far, but to stimulate further investigations to yield more potent and specific anticancer drugs. Abstract: Protein biosynthesis is a vital process for all kingdoms of life. The ribosome is the massive ribonucleoprotein machinery that reads the genetic code, in the form of messenger RNA (mRNA), to produce proteins. The mechanism of translation is tightly regulated to ensure that cell growth is well Citation: Pellegrino, S.; Terrosu, S.; sustained. Because of the central role fulfilled by the ribosome, it is not surprising that halting its Yusupova, G.; Yusupov, M. Inhibition of the Eukaryotic 80S Ribosome as a function can be detrimental and incompatible with life. In bacteria, the ribosome is a major target Potential Anticancer Therapy: A of inhibitors, as demonstrated by the high number of small molecules identified to bind to it. In Structural Perspective. Cancers 2021, eukaryotes, the design of ribosome inhibitors may be used as a therapy to treat cancer cells, which 13, 4392. https://doi.org/10.3390/ exhibit higher proliferation rates compared to healthy ones. Exciting experimental achievements cancers13174392 gathered during the last few years confirmed that the ribosome indeed represents a relevant platform for the development of anticancer drugs. We provide herein an overview of the latest structural Academic Editor: Mikael S. Lindström data that helped to unveil the molecular bases of inhibition of the eukaryotic ribosome triggered by small molecules. Received: 10 August 2021 Accepted: 26 August 2021 Keywords: ribosome; protein synthesis inhibition; anticancer drugs; X-ray crystallography; cryo-EM; Published: 31 August 2021 drug development Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. The ribosome is the universal ribonucleoprotein machinery that translates the genetic message stored in the mRNA into proteins. Its function is highly conserved and tightly regulated in all domains of life. The ribosome is composed of two subunits, one large ribosomal subunit (LSU; 50S in bacteria and 60S in eukaryotes, depending on their sedimen- Copyright: © 2021 by the authors. tation coefficient (Svedberg unit)) and a small ribosomal subunit (SSU; 30S in bacteria and Licensee MDPI, Basel, Switzerland. This article is an open access article 40S in eukaryotes). However, its composition varies remarkably between prokaryotes and distributed under the terms and eukaryotes. Ribosomes in bacteria are constituted by three types of ribosomal RNA (rRNA) conditions of the Creative Commons and 54 individual ribosomal proteins (RPs), reaching a molecular weight of approximately Attribution (CC BY) license (https:// 2.5 MDa. In eukaryotes, instead, ribosomes exist as much more complex machineries. In creativecommons.org/licenses/by/ the model organism Saccharomyces cerevisiae, for instance, the ribosome is made of four 4.0/). types of rRNA and 79 individual RPs, reaching a molecular weight of 3.3 MDa. Further Cancers 2021, 13, 4392. https://doi.org/10.3390/cancers13174392 https://www.mdpi.com/journal/cancers Cancers 2021, 13 2 of 21 Cancers 2021, 13, 4392 2 of 19 made of four types of rRNA and 79 individual RPs, reaching a molecular weight of 3.3 compositional differences exist between higher and lower eukaryotes, with mammalian MDa. Further compositional differences exist between higher and lower eukaryotes, with ribosomes containing an additional RP and, more importantly, 1 MDa of rRNA extensions mammalian ribosomes containing an additional RP and, more importantly, 1 MDa of rRNAcalled extensions expansions called segments expansions (ESs) segments [1,2]. During (ESs) [1,2]. the During last two the decades, last two decades, several sev research‐ eralgroups research have groups contributed have contributed with groundbreaking with groundbreaking studies to studies unveiling to unveiling the intimate the structureinti‐ mateof the structure ribosome of inthe different ribosome organisms in different and organisms shedding and light shedding on its functioning light on its during function protein‐ ingsynthesis. during protein At the beginningsynthesis. At of thisthe beginning very exciting of this period very of exciting time, X-ray period crystallography of time, X‐ray was crystallographythe principal method was the used principal to determine method theused structure to determine of the the entire structure bacterial of the ribosome entire and bacterialits individual ribosome ribosomal and its individual subunits, ribosomal as exemplified subunits, by as several exemplified works by [3 –several9]. Although works the [3–9].earliest Although low-resolution the earliest structure low‐resolution of the E. structure coli 70S ribosome of the E. wascoli 70S visualised ribosome by was cryo-EM visu‐ [10], alisedX-ray by crystallography cryo‐EM [10], X has‐ray been crystallography for a long time has the been only for techniquea long time yielding the only high-resolution technique yieldingelectron high density‐resolution maps thatelectron could density be used maps to buildthat could atomic be used models. to build Thus, atomic the first models. advances Thus,in ribosome the first crystallographyadvances in ribosome enabled crystallography describing, enabled at atomic describing, level, the at interactions atomic level, of the thetranslating interactions ribosome of the translating with its main ribosome functional with its ligands main functional such as transfer ligands such RNA as (tRNA) trans‐ and fermRNA RNA in(tRNA) bacteria and [ 4mRNA,11,12]. in In bacteria 2011, another [4,11,12]. major In 2011, breakthrough another major in the breakthrough field was achieved in theby field Yusupov’s was achieved group, whoby Yusupov’s determined group, the crystalwho determined structure ofthe the crystal eukaryotic structure 80S of ribosome the eukaryoticfrom S. cerevisiae 80S ribosomeat 3.0 Åfrom resolution S. cerevisiae [13]. at The 3.0 resultingÅ resolution model [13]. allowed The resulting the identification model allowedof a functional the identification “core” that of a isfunctional conserved “core” with that prokaryotes is conserved and with is prokaryotes responsible and for is tRNA responsibleand mRNA for binding, tRNA and mRNA mRNA decoding binding, and mRNA peptidyl decoding transferase and peptidyl reaction transferase [1,13]. The re larger‐ actionnumber [1,13]. of RPs The and larger the number additional of RPs ESs and are the mainly additional restricted ESs toare peripheral mainly restricted regions to of the peripheraleukaryotic regions ribosomes of the and eukaryotic suggested ribosomes to be exclusively and suggested involved to be in exclusively regulation involved of ribosomal infunctions regulation [1 ].of ribosomal functions [1]. TheThe protein protein synthesis synthesis cycle cycle in inall all cells cells is characterised is characterised by three by three main main phases: phases: (1) initi (1)‐ initia- ation,tion, wherewhere thethe 550′ endend of of the the mRNA mRNA is is scanned scanned by by the the SSU SSU until until the the initiation initiation codon codon (AUG) (AUG)is recognised; is recognised; (2) elongation, (2) elongation, where where LSU LSU joins joins the the SSU SSU to to yield yield a translationa translation competent com‐ petentribosome. ribosome. At this At step, this step, decoding decoding of mRNA of mRNA drives drives the the sequential sequential addition addition of of amino amino acids acidscarried carried by the by tRNAs, the tRNAs, and and peptide peptide bond bond formation formation occurs occurs in in the the peptidyl peptidyl transferase transferase centre centre(PTC); (PTC); (3) termination (3) termination and and recycling, recycling, where where the the ribosome ribosome encounters encounters aa stopstop codon and andtriggers triggers release release of theof the nascent nascent polypeptide polypeptide chains chains and and subunit subunit splittingsplitting (Figure 11))[ [1].1]. Figure 1. Protein synthesis inhibitors target several steps of translation. Scheme reporting the Figure 1. Protein synthesis inhibitors target several steps of translation. Scheme reporting the dif‐ ferentdifferent phases
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