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Home , George Smith (chemist), Joachim Frank, John Kendrew, Venki Ramakrishnan

Nobel prize ’s Nobel molecule factory Three scientists who revealed the structure and workings of the – the cellular machinery that turns genetic information into – have shared the 2009 in . Phillip Broadwith unravels the story NICOLLE RAGER FULLER, NATIONAL FOUNDATION SCIENCE NATIONAL FULLER, RAGER NICOLLE

42 | Chemistry World | November 2009 www.chemistryworld.org Wandering through the Laboratory molecules,’ he says, ‘and those breakthroughs at this time was of Molecular Biology (LMB) in In short molecules follow chemical laws, so Yonath’s use of cryo- , UK, it is easy to see  The 2009 Nobel prize understanding how those molecules – freezing crystals to protect how this lab, which is funded by for chemistry goes to Ada work becomes a chemical problem.’ them from damaging free radicals the Medical Research Council Yonath, Tom Steitz and And the ribosome is certainly no produced by x-rays. (MRC), has produced so many for small problem – it has a molecular But having good quality crystals Nobel laureates – fourteen in total, solving the structure of weight of 2.5 million Daltons and was only part of the battle – there split evenly between chemistry and the ribosome around a million individual atoms was still the issue of the so-called medicine or physiology. The place  are found to pinpoint. Nearly two thirds of ‘phase problem’, and this was where hums with activity and every corner in all cells and translate that mass is RNA, and the rest is Steitz and Ramakrishnan came to is filled with experimental apparatus. genetic information in a complex made up of around 50 the fore. To get enough information I’m visiting the labs just a couple of the form of RNA into individual proteins divided into two to build an accurate molecular map days after the announcement of the functional proteins subunits, so it’s no real surprise that from an x-ray diffraction pattern, 2009 Nobel for chemistry, shared by  Ribosomes are getting accurate structural data took explains Ramakrishnan, you need the LMB’s Venkatraman (‘Venki’) important drug targets nearly twenty years. to know both the intensity of the Ramakrishnan; Thomas Steitz from for new , diffracted x-rays, but also their , US; and particularly against Bicycles and sleeping bears phase – where they sit in the pattern of the Weizmann Institute of Science multi-drug resistant It was Yonath’s work that really of peaks and troughs that makes up in Rehovot, Israel; but it’s business strains laid the foundation for solving the x-ray wave. as usual in the laboratories, with structure of the ribosome. Shortly The traditional way of solving this researchers patiently teasing out the after the announcement of the prize, problem, explains Ramakrishnan, intricate details of the machinery of Yonath told the Nobel foundation is to incorporate heavy atoms that life. that her inspiration came from diffract x-rays in very defined ways, The three winners of this year’s thinking about hibernating polar such as mercury, into the crystal SKr10 million (£880 000) prize are bears. ‘Because of a bicycle accident, and then compare the diffraction credited with pinning down the I had some free time and I had to patterns with and without these structure of ribosomes – the recover and I read a lot’ she said. heavy atoms. ‘This technique of factories found in every that She explained how bears pack away isomorphous replacement was translate the four-letter genetic code their ribosomes during hibernation originally used by and of nucleic acids (DNA and RNA) into to preserve them – otherwise they here at the LMB to the 20 or so amino acid members of would degrade and there would be solve the structures of haemoglobin the protein alphabet (see top box none left to make new proteins when and , for which they p44). For this reason, Ramakrishnan the bears woke up in the spring – and received the 1962 Nobel prize for explains, ribosomes have been of how this picture of close-packed chemistry,’ he adds, ‘but to begin central importance in biology ever ribosomes inspired her to find with it wasn’t clear that this would since their discovery in the 1950s. ways of crystallising them while work for the ribosome.’ ‘Virtually every molecule in the cell preserving their activity. Steitz and Ramakrishnan took was either made by the ribosome or In the 1980s, Yonath’s group slightly different approaches to by enzymes that were themselves managed to get the first useful solving the phase problem. Steitz made by the ribosome,’ he says. crystals of the larger subunit of the looked at refining the heavy atom But Ramakrishnan is also quick ribosome from very robust bacteria. cluster techniques used by Yonath, to point out that, even though the These initial crystals were fragile and got the first really credible action of the ribosome is centrally and prone to damage from the x-rays phase information for the larger important to biologists, deciphering used to probe their structure, but subunit of the ribosome. On the its structure and relating that to the group persisted and developed other hand, Ramakrishnan focused its function at a molecular level is their crystallisation techniques on the smaller subunit and explored just as much chemistry as biology. to get better and better resolution anomalous scattering – a new ‘Underlying all of biology are x-ray images. One of the biggest idea made possible by the advent ‘Virtually every molecule in a YALE UNIVERSITY YALE cell was made by the ribosome PELLETIER MICHELINE or by enzymes made by the BIOLOGY MOLECULAR OF LABORATORY ribosome’

From left: Tom Steitz, Venki Ramakrishnan and Ada Yonath www.chemistryworld.org Chemistry World | November 2009 | 43 Nobel prize The central dogma friends and collaborators.’ This is the second time in three years that the chemistry Nobel has been awarded for the crystallography of a protein molecule. Roger Kornberg, who won the 2006 prize for his work on the structure and function of RNA polymerase – the enzyme responsible for transcribing DNA into RNA – told Chemistry World that this year’s award only serves to further underline the importance of chemistry as the basis for biology. ‘It calls attention to the importance of structure for Ribosomes translate genetic information to functional proteins understanding both chemistry and biology – particularly atomic The so-called ‘central dogma’ two subunits, and read, three Each ribosome can form 10 structure,’ he says. of biology, ‘DNA makes RNA nucleotide bases at a time. As the to 20 peptide bonds per second Kornberg also recognises that makes protein’, was formalised ribosome ratchets its way along and has built-in error checking the work done by this year’s by in 1970. the mRNA strand, each set of mechanisms to ensure that winners, particularly Yonath, is It describes how genetic three bases, or codon, is paired it only makes on average one not just relevant to the ribosome. information stored in the form of up with its complementary anti- mistake for every 100 000 ‘Yonath undertook this long before DNA is converted into functional codon on a transfer RNA that amino acids added to a peptide anyone believed it was feasible, molecules: ‘RNA makes protein’ delivers the appropriate amino chain. The whole process is and the contributions she made are is where the ribosome comes in. acid to the growing peptide orchestrated by a multitude of important for the technical basis After DNA is transcribed into chain. Once it reaches a stop helper that bind of their work, ours and what many messenger RNA in the cell’s signal on the mRNA, the peptide the ribosome at different stages other people do today.’ He adds that nucleus, the mRNA strand is released and the ribosome falls of the cycle, and it is these that it was Yonath who recommended travels to the ribosome, where apart to free the mRNA and find a much of the current research on to him the appropriate heavy atom it is clamped between the new one to translate. ribosomes is now focused on. clusters to use to solve the structure of RNA polymerase. of synchrotron radiation, which race between the groups working on On the shoulders of giants gave researchers access to tunable the two different subunits in quite Since the number of winners for wavelengths of x-rays that would friendly terms, but he remembers any Nobel is limited to three, there interact more specifically with 1999 to 2000 as a ‘tense and actually are many researchers who have lanthanides or other special atoms rather unpleasant’ period when made seminal contributions to our introduced into the crystals. ‘We his own group was in almost direct understanding of the ribosome who used heavy atoms to get going,’ competition with Yonath’s to solve might be considered to have missed says Ramakrishnan, ‘and in the end the smaller subunit structure. He out. In a press conference shortly [Steitz’s group] used anomalous adds that it is important to make sure after the prize announcement, Steitz scattering as well, so it all seemed to that competition doesn’t detract was quick to laud the work of his converge.’ from scientific progress, saying ‘My long-time collaborator at Yale, Peter attitude was to stick to the science – I Moore. Ramakrishnan points to a Compete or collaborate? have some misgivings about these series of lower resolution ‘snapshot’ With three groups working to awards in general, because they can structures produced by Harry Noller solve the structures, there was make people behave unprofessionally from the University of California, inevitably an element of competition. and cause divisions among people Santa Cruz; and the cryo-electron Ramakrishnan describes the informal who really should be the best of microscopy work of from the Wadsworth centre in The target of all targets Albany, New York, which helped to visualise how the ribosome changes Because of its crucial role in the structure of the ribosome is in the shape as it works. survival of cells, and the differences fight to overcome resistance Both Ramakrishnan and Kornberg between bacterial and human in bacteria. ‘We call the ribosome the also point out that technological versions, the ribosome is an important target of all targets,’ says Froshauer, advances played a large part in target for antibiotics. About half of all ‘and the crystal structure provides us their success – and Ramakrishnan antibiotics discovered so far target the with a wealth of three-dimensional notes how fitting it is that Willard bacterial ribosome. In 2000, Steitz chemistry to help us understand Boyle and of Bell and Ramakrishnan teamed up with a where known antibiotic classes Laboratories in New Jersey received group of colleagues, including Peter act on the ribosome, and then to ‘Understanding the 2009 physics Nobel for their Moore and Harry Noller, to found spin- design something new that would be structure is invention of the charge-coupled out company Rib-X Pharmaceuticals. more active against drug-resistant device (CCD) sensor, as it was this Susan Froshauer, a molecular ribosomes.’ Rib-X is developing a new important for that really pushed the power of geneticist who left Pfizer to head oxazolidinone antibiotic, radezolid, understanding x-ray detection, allowing data to up Rib-X, told Chemistry World which is currently performing well in be collected digitally and making it how important the high-resolution Phase II clinical trials, she adds. both biology much easier to analyse and visualise and chemistry’ such complex structures. 44 | Chemistry World | November 2009 www.chemistryworld.org