From the genetic code to new antibiotics

Biochemist Christine Dunham and her colleagues have a new paper in PNAS illuminating a long-standing puzzle concerning ribosomes, the factories inside cells that produce proteins.

Ribosomes are where the genetic code “happens,” because they are the workshops where messenger RNA is read out and proteins are assembled piece by piece. As a postdoc, Dunham contributed to Nobel Prize-winning work determining the molecular structure of the ribosome with mentor Venki Ramakrishnan.

Ribosomes are the workshops for protein synthesis and the targets of several antibiotics

The puzzle is this: how messenger RNA can be faithfully and precisely translated, when the interactions that hold RNA base pairs (A-U and G-C) together are not strong enough. There is enough “wobble” in RNA base pairing such that transfer RNAs that don’t match all three letters on the messenger RNA can still fit.

Scientists knew that the ribosome performs proofreading – it inspects the messenger RNAs and transfer RNAs to make sure that everything lines up the way it should before continuing with protein production. The new paper provides insight into how that proofreading takes place.

One way to understand the mechanism of ribosome proofreading is to look at how antibiotics such as streptomycin work. Streptomycin forces ribosomes to make mistakes, interfering with bacterial growth. (Human ribosomes are different enough from bacterial ribosomes that the antibiotic doesn’t affect us as much.)

It is possible to isolate mutant bacteria that are resistant to streptomycin or even dependent on it. The mutations responsible for this effect make ribosomes even more picky.

Working with Dunham, graduate student Crystal Fagan and colleagues determined the structure of two kinds of pickiness-mutant ribosomes by X-ray crystallography. Having a three-dimensional picture of these mutants helps scientists see how the different parts of the ribosome interact and how those interactions add to ribosome fidelity.

Dunham notes that ribosome structural studies could aid in the discovery of new antibiotics. The federal government has been pushing to speed the approval of new antibiotics needed to counter the spread of bacteria that have become resistant to existing drugs.



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