β2AR: old horse’s new tricks

It’s almost four years since the Nobel prize in chemistry went to Brian Kobilka and Robert Lefkowitz for their contribution in our understanding of G protein-coupled receptor (GPCR) signaling. They did their most exciting work by studying β2 adrenergic receptor (β2AR). Yet, despite the titanic efforts, the receptor still holds lots of secrets from us. Continue reading “β2AR: old horse’s new tricks”

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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.

Epi-epigenetics: RNA methylation (updated)

Two papers appeared online on February 10th, to claim the first whole-transcriptome study of specific RNA modification, N1-methylation of adenine (m1A). To both teams’ credits, they cited each other as they learned about “competing” study.  Both papers, Li, Xiong et al. in Nature Chemical Biology and Dominissini, Nachtergaele, Moshitch-Moshkovitz et al. in Nature, overlap quite significantly but also complete each other in several aspects, and give starting insights into the role of RNA methylation in gene regulation. Continue reading “Epi-epigenetics: RNA methylation (updated)”

Short life of biological dogmas

When you read a molecular biology textbook, it’s hard not to be amazed by the elegance and precision of cellular machinery. Everything is so logical, sequential, and organized to work properly. DNA templates self-copy and encodes RNA, which encodes proteins that do all kinds of work in a cell and organism. Francis Crick, who postulated this sequence, coined a term ‘the central dogma’ for it. And ever since ‘dogma’ became a buzzword for any fundamental assumption in molecular biology. But as with many assumptions in physics in the beginning of XX century, now many of these biological ‘dogmas’ are becoming obsolete. A recent review in Nuclear Acids Research discusses the premises for another dogma to fall.
Continue reading “Short life of biological dogmas”

The database of databases

Today chemical biology generates new high-throughput methods of studying biomolecules almost as quickly as organic chemists report total syntheses. Whole genome, transcriptome, proteome, lipidome, glycome etc. analyses are flourishing and delivering vast amounts of data. Bioinformaticist are trying to cope with the data flow by archiving them in various databases. This has led to a situation when the number and diversity of databases became incomprehensible for a human being. Continue reading “The database of databases”

Epigenetic ant reprogramming

Epigenetics is an exciting but a weird area. It’s well recognized that messing with chromatin and chemical modifications of nucleic acids has profound consequences at the cellular and organism levels. But for me the mechanistic rationale for targeting epigenome pharmacologically was always somewhere close to throwing a monkey wrench into the clockworks and watching what will happen. It seems (not surprisingly) that in fact the effects are more predictable. Continue reading “Epigenetic ant reprogramming”

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”