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Making Drugs Fit

September 12, 1998
Louisiana State University
Good health isn't just good food and exercise. Ultimately, it's the result of hundreds of thousands of chemical reactions that go on constantly inside our cells.

BATON ROUGE -- Good health isn't just good food and exercise. Ultimately, it's the result of hundreds of thousands of chemical reactions that go on constantly inside our cells.

Understanding what goes on in the ribosomes -- the protein factories inside our cells that produce not only the chemicals that make our bodies work, but the components of our organs, bones and muscles -- is the work of LSU analytical chemist Patrick Alan Limbach.

Limbach is head of a team that is researching the exact shape of nucleic acids -- reactive bits of DNA and RNA that put together the proteins that make up most of our bodies. This knowledge is basic to understanding how proteins are made at the cellular level and what can be done if things go wrong.

"When something mutates the DNA, it instructs the RNA to make the wrong protein, or it fails to tell the RNA to stop making something," Limbach said. He likens DNA to the hard drive of a computer, which holds all the instructions for running the program, and RNA to the operating system, which carries out the instructions. Proteins are the output -- what appears on the computer screen or printer.

RNA makes proteins by a complicated and harmonious series of reactions among chemicals in the cellular environment. These reactions take place at the chemically active bends and folds in the long RNA molecule. "If we know the shape of the molecule where a reaction is taking place, we can design a drug to fit that shape and, for instance, stop the reaction," Limbach said.

"Ribosomal RNA is RNA that is in the ribosome, where proteins are made. The ribosome is the protein factory of the cell. Initially, DNA is converted to mRNA, messenger RNA. That's the message from the gene. The message goes into the ribosome where things known as tRNAs have amino acids attached to them. The amino acids are the building blocks for the proteins. The ribosomal RNA is the scaffolding on which the mRNA and the tRNA build the protein."

Seeing the structural details of the ribosomal RNA is the key, he said.

"We want to be able to tell somebody, 'We know that this particular site on the ribosomal RNA is crucial for this protein to be made.' If we can block that site or change the structure of it by twisting or turning it a little bit so something can't get in there and dock with it, that would work. That would be the societal health benefit to what we're trying to do."

Limbach's long-term goals are to understand the three-dimensional structure of ribosomal RNA with the goal of creating drugs that do their work with pinpoint accuracy.

"A lot of drugs are known to go in and bind to different sites on the RNA molecule and prevent other reactions from occurring, but the discovery and development of most drugs is hit and miss. The developers don't know why it works; they just care that it does what it's supposed to do. The chemist in me is interested in understanding at a molecular level what is going on during protein synthesis."

To this end, Limbach and his graduate students have designed and built a mass spectrometer to help determine what the molecule looks like. "If we had to buy this machine, it would cost about $500,000," he said. The instrument is a large, stainless-steel barrel with powerful magnets inside, which breaks up the molecule with a laser and separates the different pieces by weight.

"Mass spectrometry is a very sensitive technique. You change the sample to a gaseous state and put a charge on the molecules, then you give them an electrical or magnetic push and let them drift. Heavier particles hit the detector later than lighter ones, and you can determine how heavy the particle is by how long it takes to hit," Limbach said.

Using different chemical and mathematical techniques, the scientists then determine what the molecules are and in what order they are arranged. That's the "primary structure" of the piece of RNA that Limbach is looking for.

"The real strength of our approach compared to other methods of structural analysis is in the ability to identify components of RNA with unique structures. These modified molecules may play a significant role in the chemical reactivity of the ribosome. There are no other current methods with the ability to identify modifications to the primary RNA structure," Limbach said.

"The long-term goal of our work is to understand the three-dimensional structure of these things, and we do that by working with people like Kathy Morden of LSU who does nuclear-magnetic resonance imaging to get the three-dimensional structure."

Limbach's work on ribosomal RNA is being funded by a $697,000 National Institutes of Health grant and by a $144,000 Board of Regents Support Fund grant.

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Louisiana State University. "Making Drugs Fit." ScienceDaily. ScienceDaily, 12 September 1998. <>.
Louisiana State University. (1998, September 12). Making Drugs Fit. ScienceDaily. Retrieved May 22, 2017 from
Louisiana State University. "Making Drugs Fit." ScienceDaily. (accessed May 22, 2017).