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Work on hammerhead ribozymes with Bill Scott


Experiments with lead enzyme
Aaron Klug Scientist
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When we were working on tRNA, when we made heavy atom derivatives one of the derivates we made was adding lead, lead acetate, to tRNA crystals and when we looked for the lead in the crystals... we couldn't find any. We did find some positive peaks, we also found a lot of negative peaks which means either the density had moved or been removed and I wondered about that and I began reading about lead and I discovered that lead, actually I knew this because we'd used before, that the lead could hydrolyse the nucleic acids at pH7, that was pretty important. You had to go... if you went below pH7 it didn't work. Now this was well known, in fact I had totally forgotten that when we were working on Turnip Yellow Mosaic Virus, we had made empty shells of the virus by adding the lead acetate the very same lead acetate to the virus. And that chewed away the RNA. So it was known by quite a lot of people, and there was a kind of curiosity, later on when I raised... brought lead into the lab, Fred Sanger used it. He was actually sequencing RNA at the time and he could use lead to break it up in yet another way. He wanted to break up RNA into the random things. Now lead had this capacity because it has a PK of seven and what it does is to bring in basic, you know, OH groups which then extract protons from various enzymatic reactions, it isn't only on... they work on proteins as well. So I was mystified by this and then realised that what must be happening was that the lead must be... catalysing some chemical reaction in the tRNA and the peaks, the positive peaks probably did represent lead atoms, and the negative peaks represented regions where the chain had been cut and nucleotides removed. And so, I had a visitor, a man called Brian Hingerty at the time, Chris Looter had put onto this and indeed we found that this was the case. The lead was bound by certain sites and a passing chain of RNA close by was hydrolysing the cut and if nucleotides were removed, we actually had lots of nucleotides. So this meant that we had a metal enzyme, an RNA enzyme with metal in it. And so this aroused the interest of a man called Bill Scott, who was coming here, sort of as a post doc from the States and so he wanted to work on this lead enzyme, as we called it. It was quite important because at the time, it was a government... commission on pollution and lead was believed, of course, to bind the sulfuric ribs and proteins, so this shed a new light on how lead might act to produce damage in the brain. So in fact the Royal Commission of pollution took it up as a matter of fact, but I think the major effect is that it's the... with lead as tetra-ethyl being added to... it leads in the end to the production of more and more lead-free petrol, but that's a side issue. So when Bill Scott came, we did some more experiments together with Hingerty which showed that we could catch the lead by changing the pH, by lowering the pH we could catch the lead before it acted, then after it acted and so follow the change. But by the time that... and RNA enzymes, ribozymes as they are called, had just been discovered in processing RNA by Sydney Altman and Tom Cech in different systems, so by the time Bill Scott came, I thought that this lead enzyme is all very well, it's a kind of interesting, it's a curiosity and an oddity but it's not going to be something that you could really put to work seriously because you couldn't control... the lead would be taking up. I thought designing enzymes, putting in sites for lead, but I thought it would be best to work on the... on the structure of a natural ribozyme.

Born in Lithuania, Aaron Klug (1926-2018) was a British chemist and biophysicist. He was awarded the Nobel Prize in Chemistry in 1982 for developments in electron microscopy and his work on complexes of nucleic acids and proteins. He studied crystallography at the University of Cape Town before moving to England, completing his doctorate in 1953 at Trinity College, Cambridge. In 1981, he was awarded the Louisa Gross Horwitz Prize from Columbia University. His long and influential career led to a knighthood in 1988. He was also elected President of the Royal Society, and served there from 1995-2000.

Listeners: Ken Holmes John Finch

Kenneth Holmes was born in London in 1934 and attended schools in Chiswick. He obtained his BA at St Johns College, Cambridge. He obtained his PhD at Birkbeck College, London working on the structure of tobacco mosaic virus with Rosalind Franklin and Aaron Klug. After a post-doc at Childrens' Hospital, Boston, where he started to work on muscle structure, he joined to the newly opened Laboratory of Molecular Biology in Cambridge where he stayed for six years. He worked with Aaron Klug on virus structure and with Hugh Huxley on muscle. He then moved to Heidelberg to open the Department of Biophysics at the Max Planck Institute for Medical Research where he remained as director until his retirement. During this time he completed the structure of tobacco mosaic virus and solved the structures of a number of protein molecules including the structure of the muscle protein actin and the actin filament. Recently he has worked on the molecular mechanism of muscle contraction. He also initiated the use of synchrotron radiation as a source for X-ray diffraction and founded the EMBL outstation at DESY Hamburg. He was elected to the Royal Society in 1981 and is a member of a number of scientific academies.

John Finch is a retired member of staff of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK. He began research as a PhD student of Rosalind Franklin's at Birkbeck College, London in 1955 studying the structure of small viruses by x-ray diffraction. He came to Cambridge as part of Aaron Klug's team in 1962 and has continued with the structural study of viruses and other nucleoproteins such as chromatin, using both x-rays and electron microscopy.

Tags: Fred Sanger, Bill Scott, Brian Hingerty

Duration: 4 minutes, 53 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008