Nobel 2009: Unlocking the Mysteries of the Cell’s Protein Factories

Figuring Out What a Ribosome Looks Like Gets Three Researchers the Nobel Prize in Chemistry

by Dr. Barry Starr, Stanford University

October 16, 2009

Venkatraman Ramakrishnan, Thomas Steitz, and Ada Yonath have won the 2009 Nobel Prize in Chemistry for determining what a ribosome looks like. Even more importantly, they were able to use this finding to figure out how ribosomes actually go about making proteins. In addition, these three researchers have opened the door for the discovery of new antibiotics.

This was an amazing feat. The ribosome is a hideously complex, incredibly tiny cellular machine responsible for making all the proteins in a cell. And of course, it is these proteins that make a cell run and make every living thing who and what they are.

And yet, even though it is incredibly tiny, from a biology perspective the ribosome is huge. It is by far the largest structure ever figured out.

Imagine the cell as the dust speck that Horton discovers in Dr. Seuss’ classic, Horton Hears a Who. What these researchers have done is figured out what a complicated factory looks like in Who-ville without anyone there to describe it. They even figured out how that factory makes its widgets!

Of course it was actually much trickier than this. A ribosome is way smaller than anything in Who-ville (except maybe the Whos’ own ribosomes). Revealing the structure of a ribosome was a Herculean task worthy of a Nobel Prize.

Ribosomes are Protein-Making Factories

The ribosome is a key player in converting
gene instructions into proteins.

Ribosomes are a key part of every living thing. They are needed to convert the instructions in genes into the actions of proteins.

Everyone has heard that genes are the instructions for life. A dog is a dog because of its collection of genes. Same thing with an octopus, a bacterium, a weed, a person or an oak tree.

But the gene itself can’t do anything on its own. The instructions in the gene first need to be read by a cell and turned into a protein. The proteins then go on to give an octopus eight legs, have an oak tree photosynthesize, etc. Proteins do most everything every living thing does.

The first step in getting from gene to protein is to copy a gene’s instructions into something called messenger RNA (mRNA). This is called transcription.

The second step is for that mRNA to head over to a ribosome. There the ribosome builds a protein from the mRNA’s instructions. This is called translation.

Scientists already knew a bit about translation before this work. For example, they knew that the instructions in a gene are written in a genetic code.

This genetic code is made up of four different letters—A, G, C, and T. In a gene, these letters are grouped into three letter “words” (or codons) that are strung together, one after the other.

Each of these words is a code for a single amino acid. So a gene has the instructions for a long string of specific amino acids in a specific order. And that is what a protein is—a long stretch of specific amino acids in a certain order.

A ribosome takes these three letter words and uses them to connect the right amino acids together in the right order. In the end, the cell has a protein that can do something.

Scientists also knew who the players were in translation. There was the mRNA which had the gene’s instructions. There was the ribosome where the protein was built. And there were the molecules that brought the amino acid to the ribosome—tRNAs.

There were other players too (for example the proteins that stick amino acids to the tRNAs) but these are the main three. To figure out how the ribosome connects the right amino acids in the right order, researchers needed to figure out what it looked like.

Ribosomes Use Their RNA to Make Proteins

The RNA of a ribosome
(shown in orange) connects
amino acids together
to make a protein.

The researchers used something called X-ray crystallography to do their work. First they blasted a ribosome with X-rays. Then they looked to see how the X-rays changed as they passed through the ribosome. From this they were able to infer what it looked like.

This is the same technique used to discover what DNA looked like back in the 1950’s. But DNA is much simpler than a ribosome. It is more of a hammer in Who-ville as opposed to a whole factory. No one was really sure that something as complicated as a ribosome could ever be figured out this way.

When Watson and Crick first figured out what DNA looked like, they were able to learn a lot about how it worked too. Same thing with the ribosome. From the structure, the three researchers were able to piece together how the ribosome orchestrates the making of a protein.

They could actually see where the mRNA snakes in between the two halves of a ribosome (its subunits). They could also see that three codons on the mRNA line up at three different spots in the ribosome. This holds the mRNA in place so the tRNA can bring in the right amino acid.

They could also see that the ribosome doesn’t use a protein to stick the amino acids together. Instead, it uses RNA. Which wasn’t what most people expected.

The ribosome is made up of both RNAs and proteins. Originally it was thought that the RNA provided structure and the proteins did the work of connecting the amino acids together.

Now this wasn’t crazy. Remember that proteins do most everything in a cell so it made sense that the proteins would do the ribosome’s heavy lifting. But RNA sometimes can do some of the things a protein can do. And this is what happens in a ribosome.

One reason this is interesting is because of a theory that the world started off with just RNA and that proteins and DNA came later. This certainly lends support to that idea—RNA can and does make proteins. Just as someone might predict in an RNA world.

Figuring out what a ribosome looks like had other, more practical applications too. Scientists have been able to use the structure to find new antibiotics.

Great video on translation

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Ribosome Structure Leads to New Antibiotics

Many antibiotics kill bacteria
by mucking with their ribosomes.

Antibiotics are medicines designed to treat bacterial infections and diseases. They revolutionized medicine when they first came out. Antibiotics have probably saved more lives than any other medical advance. Ever.

Antibiotics kill bacteria by exploiting differences between how human and bacterial cells work. For example, the most famous antibiotic, penicillin, works by keeping certain bacteria from making their cell walls. People don’t have cell walls and so, unless someone is allergic, penicillin has no effect on a patient.

Human and bacterial ribosomes are very similar but there are significant differences. Many antibiotics target these differences (click here for a list of antibiotics that work through the ribosome).

Recently antibiotics have become less useful because of overuse and bacterial evolution. Many bacteria are now resistant to the most common antibiotics and doctors live in fear that one will evolve that is resistant to all known antibiotics. Then humankind is back in a world where a bacterial infection can kill someone. Medicine definitely needs new antibiotics to treat these resistant bacteria.

This is where knowing what the ribosome looks like can help. Scientists can see where the antibiotic interferes with the bacterial ribosome. And they can figure out what they can do to the antibiotic to get it past the resistant bacteria and still have it work.

Tom Steitz’s company has been making new antibiotics and two of them have made it to Phase II trials. Hopefully these new antibiotics can come out before the first bacteria resistant to all known antibiotics appear.

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Content provided by the Department of Genetics, Stanford University.