Abstract
Natural products that target the eukaryotic ribosome are promising therapeutics to treat a variety of cancers. It is therefore essential to determine their molecular mechanism of action to fully understand their mode of interaction with the target and to inform the development of new synthetic compounds with improved potency and reduced cytotoxicity. Toward this goal, we have previously established a short synthesis pathway that grants access to multiple congeners of the lissoclimide family. Here we present the X-ray co-crystal structure at 3.1 Å resolution of C45, a potent congener with two A-ring chlorine-bearing stereogenic centers with ‘unnatural’ configurations, with the yeast 80S ribosome, intermolecular interaction energies of the C45/ribosome complex, and single-molecule FRET data quantifying the impact of C45 on both human and yeast ribosomes. Together, these data provide new insights into the role of unusual non-covalent halogen bonding interactions involved in the binding of this synthetic compound to the 80S ribosome.
Highlights
The ribosome is the central player in protein biosynthesis in all living organisms
As shown for its congener, CL [3], C45 binds within the large ribosomal subunit (LSU) E-site pocket (Figure 2)
Its binding impairs the entrance of the CCA-end of the tRNA into the E-site pocket during the elongation phase of protein synthesis
Summary
The ribosome is the central player in protein biosynthesis in all living organisms. In eukaryotic species, this massive (∼4.3 MDa) ribonucleoprotein assembly, which is composed of four types of ribosomal RNA (rRNA) and ∼80 ribosomal proteins, has a significant role in regulation of cell growth. This massive (∼4.3 MDa) ribonucleoprotein assembly, which is composed of four types of ribosomal RNA (rRNA) and ∼80 ribosomal proteins, has a significant role in regulation of cell growth For this reason, it is not surprising that the ribosome represents a useful target for the inhibition of proliferative cancers, often characterized by dysregulated protein synthesis [1,2,3,4,5]. Previous biochemical experiments suggested that these compounds act to hinder the elongation phase of translation, preventing P-site tRNA from proceeding further into the ribosomal E-site, thereby blocking cellular functions [8]
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