Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex

Carelli, Jordan D; Sethofer, Steven G.; Smith, Geoffrey A.; Miller, Howard L.; Simard, Jillian; Merrick, William C.; Jain, Rishi K.; Ross, Nathan T.; Taunton, Jack

doi:10.7554/elife.10222

Cited by 44 publications

(65 citation statements)

References 45 publications

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“…6b ), which is currently in a phase I clinical trial for cancer therapy. We also observed potent antiviral effects of the elongation factor-1A (eEF1A) inhibitor ternatin-4 50 ( Fig. 6b ), which may suggest that the rate of translation elongation is critical for obtaining optimal levels of viral proteins.…”

Section: Mainmentioning

confidence: 81%

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Gordon

Jang

Bouhaddou

et al. 2020

Nature

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The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

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Section: Mainmentioning

confidence: 81%

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Gordon

Jang

Bouhaddou

et al. 2020

Nature

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4,010

157

5,576

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“…However, it is not known if the translation elongation factors eEF1a and eEF2—which deliver aminoacyl-tRNAs to the ribosome and promote translocation, respectively—collaborate with Rqc2p to facilitate CAT-tail synthesis. Strikingly, we found that drugs targeting either eEF1a or eEF2 (didemnin variants ( Carelli et al, 2015 ) or sordarin ( Justice et al, 1998 ), respectively) had no effect on CAT tailing ( Figure 2C ). Because many canonical translation factors are GTPases, including eEF1a and eEF2, we also examined whether CAT tailing requires GTP hydrolysis.…”

Section: Resultsmentioning

confidence: 96%

In vitro analysis of RQC activities provides insights into the mechanism and function of CAT tailing

Osuna

Howard

et al. 2017

eLife

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Ribosomes can stall during translation due to defects in the mRNA template or translation machinery, leading to the production of incomplete proteins. The Ribosome-associated Quality control Complex (RQC) engages stalled ribosomes and targets nascent polypeptides for proteasomal degradation. However, how each RQC component contributes to this process remains unclear. Here we demonstrate that key RQC activities—Ltn1p-dependent ubiquitination and Rqc2p-mediated Carboxy-terminal Alanine and Threonine (CAT) tail elongation—can be recapitulated in vitro with a yeast cell-free system. Using this approach, we determined that CAT tailing is mechanistically distinct from canonical translation, that Ltn1p-mediated ubiquitination depends on the poorly characterized RQC component Rqc1p, and that the process of CAT tailing enables robust ubiquitination of the nascent polypeptide. These findings establish a novel system to study the RQC and provide a framework for understanding how RQC factors coordinate their activities to facilitate clearance of incompletely synthesized proteins.DOI: http://dx.doi.org/10.7554/eLife.27949.001

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“…Based on this observation, we propose a conserved mechanism (Schmeing et al., 2009) that didemnin B serves to increase the effective number of contacts between the GDP-bound G domain and domain 3 to prevent the inter-domain rotation that is necessary for eEF1A to release aa-tRNA and dissociate from the ribosome. Recently, didemnin B and ansatrienin B have been shown to compete with ternatin for binding to eEF1A (Carelli et al., 2015), and mutations in eEF1A Ala399, adjacent to the β15-β16 hairpin, were found to confer decreased sensitivity to didemnin B, ternatin, and another structurally unrelated natural product, nannocystin A (Carelli et al., 2015, Krastel et al., 2015). This suggests that these chemically diverse natural products share similar mechanisms of activity.…”

Section: Resultsmentioning

confidence: 99%

Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes

Shao¹,

Murray²,

Brown³

et al. 2016

Cell

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SummaryIn eukaryotes, accurate protein synthesis relies on a family of translational GTPases that pair with specific decoding factors to decipher the mRNA code on ribosomes. We present structures of the mammalian ribosome engaged with decoding factor⋅GTPase complexes representing intermediates of translation elongation (aminoacyl-tRNA⋅eEF1A), termination (eRF1⋅eRF3), and ribosome rescue (Pelota⋅Hbs1l). Comparative analyses reveal that each decoding factor exploits the plasticity of the ribosomal decoding center to differentially remodel ribosomal proteins and rRNA. This leads to varying degrees of large-scale ribosome movements and implies distinct mechanisms for communicating information from the decoding center to each GTPase. Additional structural snapshots of the translation termination pathway reveal the conformational changes that choreograph the accommodation of decoding factors into the peptidyl transferase center. Our results provide a structural framework for how different states of the mammalian ribosome are selectively recognized by the appropriate decoding factor⋅GTPase complex to ensure translational fidelity.

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Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex

Cited by 44 publications

References 45 publications

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

In vitro analysis of RQC activities provides insights into the mechanism and function of CAT tailing

Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes

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