Ribosome stalling as gene regulation?

Another cool paper from Mankin lab showed up in Nature Chemical Biology. This time researchers were looking at the detailed mechanism of translational arrest by two macrolide antibiotics, erythromycin and telithromycin.

ERY-TEL

Via series of mutations authors identified a single amino acid in the nascent peptide chain that determines selectivity and promiscuity of ribosome stalling by either of two antibiotics. To prove their point, they created an unnatural mutant gene with engineered selectivity to TEL.

While major implications of the study are dealing with antibiotic resistance and ways to overcome it, the authors coin an interesting evolutionary speculation. They suggest that the ribosome stalling could be another mechanism for gene regulation. In this case the sequence of some peptides could evolve in order to recognize small molecules during translation of the protein itself. And this could be another way to react on the environmental stimuli.

I guess that calls for another whole-transcriptome and cross-species genomic mining study for identification of such sequence−cofactor pairs.

By the way, a rare case, they did molecular dynamics simulation but didn’t include any pretty picture from it in the main text of the manuscript! That’s what happening when one has enough experimental data.

Synthetic lethality as drug discovery platform

One of the features of drug design in the -omics era is the shift from target- and structure-based to function-based drug discovery, when the active compound is identified simultaneously or before the mechanism of action.

A new report in Nature Chemical Biology describes an interesting blend of small molecule high-throughput screening with genetic screening via synthetic lethality. As one might guess, the approach is dealing with cellular death. Traditional ‘simple’ genetic screen identifies individual genes that are critical for cell survival. The principle of synthetic lethality is somewhat different. Scientists seek gene pairs or networks that are crucial in combination but which could be silenced individually without jeopardizing essential cellular functions. Previously it was applied for the discovery of anticancer therapeutics. This time the team from Harvard Medical School aimed at Staphyllococcus aureus. Continue reading “Synthetic lethality as drug discovery platform”