8/8/2019 Ribosome Unraveled: A Q&A with Nobelist Thomas Steitz (from Scientific American Oct 12, 2009)

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Ribosome Unraveled: A Q&A with Nobelist Thomas Steitz

One of the winners of this year's Nobel Prize in Chemistry describes the efforts that went into piercing the ribosome's secrets

By Laurie Wiegler October 12, 2009 0

NOBEL WINNER Thomas Steitz help determine thestructure of the ribosome. Image: Michael Marsland/Yale University.

8/8/2019 Ribosome Unraveled: A Q&A with Nobelist Thomas Steitz (from Scientific American Oct 12, 2009)

http://slidepdf.com/reader/full/ribosome-unraveled-a-qa-with-nobelist-thomas-steitz-from-scientific-american 2/5

Thomas Steitz, Sterling Professor of Molecular Biophysics and Biochemistry and Professor of Chemistry at Yale University and Howard Hughes Medical Institute Investigator, receives one-third of this year's Nobel Prize in Chemistry for elucidating the structure and function of theribosome, the protein-making factory of the cell. Joining him are Venkatraman Ramakrishnan of the MRC Laboratory of Molecular Biology in Cambridge, England, and Ada Yonath at the

Weizmann Institute of Science in Rehovot, Israel, who also worked on the problem.

The Nobel not only recognizes 69-year-old Steitz for his seminal work on the ribosome, but alsofor his work's ramifications, including the promise in bettering the next generation of antibiotics.The award comes after numerous plaudits, including the 2007 Gairdner Foundation InternationalAward, the same won the previous year by his wife Joan, a fellow Yale biochemist. Steitz's other honors include the Lewis S. Rosenstiel Award for Distinguished Work in Basic MedicalSciences and the American Association for the Advancement of Science Newcomb ClevelandPrize, both in 2001.

We asked Steitz about his studies of the ribosome and its implications,

You mapped each of the ribosome's 100,000 atoms, using synchrotron-generated x-rays,which scattered off the atoms in the ribosome and hence revealed their locations. Whatwere some of the challenges you faced in conducting such x-ray crystallography onribosomes?

One of the problems with the ribosome is that it’s big, and so whereas a mercury bound to asmall molecule like myoglobin gives a big signal, mercury bound to the ribosome does not.[Adding metals such as mercury boosts the scattering and hence the signal strength.]

So we used a heavy atom cluster containing 18 tungsten atoms bound to each other, so they’revery close to each other. At low resolution they scatter essentially as one atom. That gave a

strong signal, which got us started.

During the cell's protein-making process, ribosomes recognize the genetic code as relayedby messenger RNA and then, with the help of transfer RNA, assemble amino acids into aprotein—a process called translation. What particular ribosome question were you lookingto answer when you began your research in the mid-1990s?

8/8/2019 Ribosome Unraveled: A Q&A with Nobelist Thomas Steitz (from Scientific American Oct 12, 2009)

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We were trying to understand the structural basis of the mechanism whereby the ribosome canrecognize [the genetic code] and the transfer RNA and match it with the messenger RNA. Suchrecognition is done in a small ribosomal subunit.

The other question was how does the ribosome catalyze the formation of the chemical bonds between amino acids attached to the transfer RNA. … That’s done on a large subunit.

What we found was this catalysis is done entirely by RNA, which is consistent with thehypothesis that the original ribosome was all RNA, which makes sense if you realize the-chicken-and-the-egg nature of the problem. You can’t make proteins starting with a protein if the

first protein is the enzyme that does it, so instead you use RNA.

You are in New Haven and your Nobel counterparts are in the U.K. and Israel. Was thegeography relevant for some reason , or was it simply your individual preeminence in thefield that caused you to work on the same problem?

We were independently working on the problem. Ramakrishnan started working on the small

subunit one when he was on the faculty at the University of Utah and then he moved toCambridge. Ada Yonath’s been in Israel and also at the Max Planckin Berlin for many, manyyears. And I’ve been here for a long time.

This all started independently, and we really worked independently as well.We paid attention to publications, but otherwise there wasn’t any collaborative communication.

But you all worked on this same project.

Same, but there are different aspects. Yonath was working on both the large and small subunit.Ramakrishan was working on the small subunit. We [at Yale] were working on the large subunit.

8/8/2019 Ribosome Unraveled: A Q&A with Nobelist Thomas Steitz (from Scientific American Oct 12, 2009)

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You began your work in 1995 and published the results in 2000. What occurred in theintervening five years?

Five years was quite fast given the scale of the problem and the technical developmentsrequired. In 1995-2000 the computation and x-ray data collection tools were largely developed, but numerous changes in data collection technology in the late '90s helped a lot.

Patrick Sung, chair of the Yale department of molecular biophysics and biochemistry, wasquoted as saying your work will be put to practical use because "bacteria cannot survivewithout a functional ribosome" and your "studies will likely lead to more efficacioustreatment of bacterial infections via the design of new antibiotics that target the ribosome."And you established a large biopharmaceutical firm, Rib-X (pronounced "rye-bex") here

in New Haven that seeks to develop new antibiotics. Why are the results of your researchexciting to someone at one of the pharmaceutical companies seeking to craft newantibiotics?

It looks to me that the ones Rib-X is designing by piecing together portions of existingcompounds work very effectively, but it's hard to know what one should call "new." It's a newcompound in the sense that it hasn't been used before. And they have different properties.

Bacteria evolve, and so they become resistant to existing drugs. Sometimes they revert,depending on how damaging the mutation is to the life cycle of the bacteria. Mutations that giverise to resistance against particular compounds do increase and that is why you constantly haveto have new ones.

Would you compare the discovery of ribosome structure to something as lofty as say, thediscovery of DNA's double helix?

I don't think it will have as wide an impact. What was important about that discovery is not thestructure, so to speak—the pitch and rise per residue and all that—as interesting as all that is.What was important is the base pairing, which then gives you immediately the answers to howyou copy the DNA and go on to the next generation. That had major impact, it seems to me.

8/8/2019 Ribosome Unraveled: A Q&A with Nobelist Thomas Steitz (from Scientific American Oct 12, 2009)

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That leads to your own work and your great achievement. Is there some aspect of yourribosome work that you hope will resonate most with humanity, long after we're bothgone?

That's a hard question.

You don't have to answer it.

It depends. If you're talking about biological scientists, and people trying to understand structureand function and perhaps designing new molecules, it can be useful, but I doubt it will have thesame resonance as the double helix. That's a hard one to compete with.