The tiniest scale yields the biggest prize
Nobel Prize is awarded for atomic-level studies
of cell structure basic to life
A telephone ringing before daybreak is unlikely to appear on anyone’s list of favorite sounds, but for Thomas A. Steitz, Ph.D., it may now rank with the sweetest music.
In the early morning hours of October 7, Steitz, Sterling Professor of Molecular Biochemistry and Biophysics, learned in a call from Sweden that he would share the 2009 Nobel Prize in Chemistry for his seminal research on the structure of the ribosome, a cell organelle that is vital to protein synthesis and to the action of many antibiotics.
Later that day, at a press conference packed with media representatives and well-wishers in the President’s Room of Yale’s Woolsey Hall, a reporter asked Steitz where he was when he heard the news.
“I was in bed,” a cheerful Steitz deadpanned, to laughter from the crowd. “It was 5:30 a.m., maybe a little bit before that. The telephone rang and Joan [Joan A. Steitz, Ph.D., Thomas Steitz’s wife, also Sterling Professor of Molecular Biochemistry and Biophysics] answered it and said, ‘It’s for you.’ So I went over and it turned out to be from Stockholm. Very exciting.”
Some of Steitz’s apparent calm may have been due to the fact that his name has been frequently included on informal short lists of potential Nobelists ever since 2000, when he and a team including longtime Yale collaborator Peter B. Moore, Ph.D., Sterling Professor of Chemistry, published a pair of papers in the journal Science on the structure and function of the ribosome as determined by X-ray crystallography.
The ribosome is an asymmetrical structure consisting of a large and small subunit. In the two Science articles, hailed as “landmark publications” in an accompanying commentary, Steitz and colleagues described and depicted the structure of the large, protein-synthesizing portion of the ribosome in Haloarcua marismortui, an evolutionarily ancient, single-celled, “extremophile” organism that thrives in the highly salty, oxygen-poor depths of the Dead Sea. Extremophiles have played an important role in the recent history of structural biology (see related story) because their proteins are unusually stable in the laboratory and relatively easy to crystallize for X-ray analysis.
Since structures as basic to life as the ribosome have been highly conserved over the course of evolution, the insights that Steitz and colleagues gained in their studies of H. marismortui have broad ramifications. In a notable example, many widely prescribed antibiotics work by binding to the ribosomes of infectious bacteria and disrupting their function, and knowledge of ribosome structure is now leading to better strategies to combat drug-resistant bacterial strains.
In this image from one of the classic Science articles published in 2000 by Thomas Steitz and colleagues, the large subunit of the ribosome is seen to be primarily composed of RNA helices (gray), interspersed with stabilizing protein backbones (gold). |
By providing the first detailed 3-D reconstructions of the ribosome (Steitz and colleagues imaged the H. marismortui ribosome at a resolution of 2.4 angstroms—for comparison, this sheet of paper is about 1 million angstroms thick), the Steitz lab conclusively showed that the ribosome was not an RNA framework that made it possible for protein enzymes to catalyze the chemical reactions involved in synthesizing other proteins, but the opposite: in the ribosome, proteins provide a stabilizing scaffold for a dense mass of RNA helices that catalyze these reactions themselves (see image above).
In addition to settling these structural questions, the Science papers provided intriguing evidence in support of the “RNA world” hypothesis, which proposes that life forms dependent on RNA as both an information-carrier and enzyme were abundant before the rise of DNA and protein-based organisms.
Steitz shares the Nobel Prize equally with Ada E. Yonath, Ph.D., of the Weizmann Institute of Science in Israel, who pioneered the crystallization of the H. marismortui ribosome, and Venkatraman Ramakrishnan, Ph.D., of the MRC Laboratory of Molecular Biology in Cambridge, United Kingdom.
Ramakrishnan, who was a postdoctoral associate in Moore’s Yale lab 30 years ago (“It’s good to see one’s ‘children’ doing well,” said Moore) went on to solve the structure of the small subunit of the ribosome in another extremophile, Thermus thermophilus, a bacterial denizen of super-hot deep-sea vents.
Along with Moore and William L. Jorgensen, Ph.D., Sterling Professor of Chemistry, Steitz is a co-founder of Rib-X Pharmaceuticals, Inc., a New Haven–based drug discovery company that is applying knowledge of ribosome structure to the creation of new, more effective classes of antibiotics.
At the October press conference, Steitz made a plea for the support of basic science, pointing out designing antibiotics was “the furthest thing from our minds” when his team first decided to crack the secrets of ribosomal structure.
Recalling the daunting technical challenges that faced him and his colleagues, he said, “It seemed a little like climbing Mount Everest. We knew it was doable in principle but we did not know if we would ever get there.” But when he saw a detailed image of the ribosome for the first time, he added, it was “the most exhilarating moment I have experienced in science.” 
|
