BioEd Online

Three molecular biologists who mapped the structure and inner workings of the ribosome — the cell's machinery for churning out proteins from the genetic code — have won the Nobel Prize in Chemistry.

Venkatraman Ramakrishnan, who works at the Medical Research Council's Laboratory of Molecular Biology in Cambridge, UK; Ada Yonath of the Weizmann Institute of Science in Rehovot, Israel, and Thomas Steitz at Yale University in New Haven, Connecticut, share the prize equally.

"I'm in a bit of shock at the moment," Ramakrishnan told Nature shortly after the prize had been announced. "So many people contributed, and the ribosome is so important, that I am just pleased to be one of the three."

His and Steitz's groups used X-ray crystallography to solve increasingly high-resolution structures of different ribosomes — mostly from simple organisms such as bacteria — which were published in the late 1990s and early 2000s. Yonath paved the way for these studies by creating the first ribosome crystals in the 1980s. From such structures, researchers have worked out how the ribosome grabs messenger RNA — transcribed from DNA — follows its amino-acid recipe, and binds these units together to produce proteins.

Get the crystal!

The ribosome — even in its smaller bacterial form — is a large and complex structure, consisting of two subunits and more than 50 different proteins. In the late 1970s, this was orders of magnitude larger than other biological molecules that had been coaxed into forming crystals, such as haemoglobin and myoglobin.

"The idea of crystallizing the ribosome was completely outrageous, but Ada had a deep-rooted belief that she knew what she was doing," says Yehiam Prior, head of the Weizmann Institute's chemistry faculty.

By using resilient organisms with particularly stable ribosomes — including salt-loving creatures from the Dead Sea — Yonath succeeded in creating three-dimensional crystals of the molecule. By hitting these with X-rays, she produced the first blurry images of the ribosome.

At that point, other teams piled in to create structures of high enough resolution to determine atomic structure. Steitz's team focused on the molecule's larger 50S subunit, which joins amino acids together into proteins, and published the first atomic-resolution structure in 2000¹. "These were very exciting times, with huge competition with other groups in the field. We had hourly discussions every day," recalls Nenad Ban, who worked in Steitz's laboratory as a postdoc but is now at the Swiss Federal Institute of Technology Zurich. Ramakrishnan's group, meanwhile, attacked the smaller 30S subunit, which latches onto mRNA — work that also culminating in a 2000 publication².

Medical meaning

"The ribosome is already starting to show its medical importance," Ramakrishnan notes. All three researchers have published analyses of how antibiotics attack bacteria by disrupting their ribosomes and so preventing them from creating proteins. Our own ribosomes, which have somewhat different structures, are left untouched.

Chloramphenicol, for example, binds to the 50S subunit's active site, preventing it from joining amino acids together, whereas erthyromycin 'constipates' the ribosome by blocking the channel through which a completed chain of amino acids is normally released into the cytoplasm to fold up.

As bacteria have evolved resistance to these antibiotics, start-up companies such as Rib-X Pharmaceuticals, based in New Haven, Connecticut, and spun out of Steitz's team, are using knowledge of the ribosome's structure to create new antibiotics, which are currently in clinical trials.

It is the third time in seven years that the chemistry Nobel has been awarded to crystallographers who have determined the structure and function of a complex biological molecule. "It does seem to be a recurring theme," says Thomas Lane, president of the American Chemical Society. But at its heart, this structural biology is "fundamentally chemistry", adds Jeremy Sanders, head of physical sciences at the University of Cambridge, UK, "even if many chemists had never heard of any of the winners".