Molecular structure reveals how the antibiotic streptomycin works

September 6, 2013 by Laura Mgrdichian  
A) A ribbon diagram of the ribosome's streptomycin binding site. B) A close-up of the rectangular area outlined in A. Streptomycin Is represented as yellow sHcks and spheres, helices are colored red, dark green, cyan, orange, and blue.

(Phys.org) —Streptomycin was the first antibiotic developed to treat tuberculosis yet until recently, scientists did not completely understand how it works at the molecular level. They knew that streptomycin blocks a critical process, the synthesis of proteins by ribosomes leading to bacterial cell death, but certain details of the interaction remained undiscovered. At Brookhaven National Laboratory's National Synchrotron Light Source, researchers have used x-ray crystallography to complete the picture.

Streptomycin is a member of a family of antibiotics that work by interrupting the function of bacteria cells' , the complex molecular machines that create proteins by linking together. Ribosomes, a major target for antibiotics that work by inhibiting the synthesis of proteins, have two main parts or "subunits."

The larger subunit does the protein building, guided by a type of RNA called messenger RNA (mRNA), which binds to it. The small subunit "reads" the mRNA and selects the matching transfer RNA (tRNA) molecule, which selects and delivers the next amino acid to the ribosome. This is where streptomycin plays a role. It binds close to the small subunit, causing it to severely misread the sequence. This results in the synthesis of random proteins, which ultimately kills the bacteria. But how this misreading occurred remained a mystery, until a recent study by researchers from Brown University and the multi-institution Northeastern Collaborative Access Team at Argonne National Laboratory (managed by Cornell University).

By creating a crystal – an ordered structure of identical units – of the small ribosomal subunit bound to mRNA in the presence of streptomycin, the researchers generated several detailed "snapshots" that revealed key molecular-level details of the interaction, ultimately showing how streptomycin impairs the function of the subunit. At NSLS beamline X25, they used a technique called x-ray crystallography, in which a beam of x-rays is aimed at the crystal, interacts with the molecules, and yields an intricate diffraction pattern. From the pattern, with the help of computer software, the group constructed visual representations of the subunit-mRNA-streptomycin complex.

In short, the researchers could "see" for the first time the subtle ways in which streptomycin distorts the structure of the subunit's decoding site, causing it to incorrectly read the mRNA. For example, streptomycin binding reduces the distance between two of the many helices that make up the subunit's molecular structure. This is particularly significant because these helices form the actual decoding site, and decoding only takes place properly if these elements are oriented exactly right with respect to the mRNA and the selected tRNA. Streptomycin binding also induces a change in the relationship between one of these two helices and a third helix, causing one to retract away from the other or "disengage."

The end result of all of these slight alterations is that streptomycin destabilizes binding between the subunit and the "correct" tRNA while simultaneously stabilizing the binding of the subunit to the "wrong" tRNA, thereby effectively removing the discrimination between the correct and the wrong tRNA. This causes havoc in the bacterial supply chain for new proteins, disrupting the bacteria reproduction and life cycle.

"Our structural studies revealed that the streptomycin induces surprisingly large distortions in the bacterial ribosome, which help us understand how this antibiotic interferes with protein synthesis in bacteria," said lead researcher Gerwald Jogl, an associate professor of biology in Brown's Molecular Biology, Cell Biology & Biochemistry Department. "Continuing from our current findings, we are now studying how mutations in bacterial ribosomes can counteract these structural rearrangements and enable bacteria to survive the otherwise lethal action of streptomycin."

This research was published in the January 15, 2013 edition of Nature Communications, under the title "A structural basis for streptomycin-induced misreading of the genetic code." Support came from the National Institutes of Health and the Department of Energy.

Explore further: Study reveals how ribosomes override their blockades

More information: www.nature.com/ncomms/journal/v4/n1/full/ncomms2346.html

Related Stories

Study reveals how ribosomes override their blockades

May 14, 2012

Ribosomes are "protein factories" in the cells of all living things. They produce proteins based on existing genetic codes stored on special nucleic acid molecules. These molecules, also called messenger RNA (mRNA) due to ...

Study reveals key step in protein synthesis

June 27, 2013

Scientists at the University of California, Santa Cruz, have trapped the ribosome, a protein-building molecular machine essential to all life, in a key transitional state that has long eluded researchers. Now, for the first ...

This image could lead to better antibiotics

June 28, 2013

(Phys.org) —This may look like a tangle of squiggly lines, but you're actually looking at a molecular machine called a ribosome. Its job is to translate DNA sequences into proteins, the workhorse compounds that sustain ...

Ribosome research takes shape

August 29, 2013

In a new state-of-the-art lab at SLAC National Accelerator Laboratory, components of ribosomes – tiny biological machines that make new proteins and play a vital role in gene expression and antibiotic treatments – form ...

Recommended for you

Findings illuminate animal evolution in protein function

July 27, 2015

Virginia Commonwealth University and University of Richmond researchers recently teamed up to explore the inner workings of cells and shed light on the 400–600 million years of evolution between humans and early animals ...

New polymer able to store energy at higher temperatures

July 30, 2015

(Phys.org)—A team of researchers at the Pennsylvania State University has created a new polymer that is able to store energy at higher temperatures than conventional polymers without breaking down. In their paper published ...

How to look for a few good catalysts

July 30, 2015

Two key physical phenomena take place at the surfaces of materials: catalysis and wetting. A catalyst enhances the rate of chemical reactions; wetting refers to how liquids spread across a surface.

Yarn from slaughterhouse waste

July 29, 2015

ETH researchers have developed a yarn from ordinary gelatine that has good qualities similar to those of merino wool fibers. Now they are working on making the yarn even more water resistant.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.