Five reasons we’re excited by how structural biology is advancing cancer research – The Institute of Cancer Research (blog)

A protein model is built into an electron density map, amino acid by amino acid. The result is a snapshot of the protein or protein complex at work. Image courtesy of Dr Sebastian Guettler.

Several research teams at the ICR are devoted to structural biology a crucial discipline in cancer research that is shedding light on some of lifes most fundamental processes. We are excited about the potential this field has to enable the discovery of brand new cancer drugs. There are five key reasons why structural biology research excites us:

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Structure of RNA polymerase II. Image credit: David Bushnell, Ken Westover and Roger Kornberg, Stanford University. CC BY-NC 2.0.

Our structural biologists explore the shapes of proteins in detail, down to the individual atom, and work out how they interlock with other proteins and potential drugs. Proteins are the drivers of all our biological processes, which are hijackedin cancer to drive cell growth and spread.

Were interested in finding out what a protein looks like in three dimensions, to better understand its function and how, in cancer cells, it can go wrong. If we can determine which parts of the protein are important for its role in normal cells and cancer cells, then our drug discovery teams might be able to design drugs that turn the protein on or off.

The SAM domain of Tankyrase self-assembles into structures resembling curled pearl strings. Image credit: Dr Sebastian Guettler.

X-ray crystallography is a technique that offers a fascinating way by which we can look at proteins to understand how they work.Dr Sebastian Guettler has used this technique to help understand which parts of certain proteins might be targets for cancer drugs.

For protein X-ray crystallography, we make a crystal containing millions of copies of our protein of interest, all slotting together in a highly ordered way. Then we irradiate the crystal with X-rays to create a map of the atoms positions.

Another technique is called electron microscopy. This means we image our protein at around 50,000 times magnification using a beam of electrons, rather than light.

Atomic model of 26S proteasome. Image from Wikipedia user FridoFoe. CC BY-SA 3.0

Several ICR-led research programmes are using the techniques mentioned above to improve our knowledge of key cancer-causing proteins. One focus is cell division normally a highly regulated process, but hijacked by cancer to drive its continued growth. Recent studies from our Division of Structural Biologyhave produced detailed maps of two major players in this process: the proteasome and the anaphase promoting complex.

These maps have advanced our understanding of how the various parts of both complexes weave together and pull apart during cell division not only in humans, but in all animals and plants.

Composite image of a low-resolution cryo-electron microscopy density map for the enzyme -galactosidase. Image credit: Veronica Falconieri, Sriram Subramaniam, National Cancer Institute, National Institutes of Health. CC BY-NC 2.0.

Some of our researchers are using a developing technology that is sparking much excitement in the field, called cryo-electron microscopy. This involves freezing and imaging samples at -180C to preserve the finest details of the protein shapes. This type of microscopy is an emerging and tremendously exciting approach in cancer drug design.

As well as offering much greater detail than it did even a few years ago, it provides the opportunity to study protein complexes in conditions closer to those in the human body which should make it much easier to design entirely new cancer drugs.

Image credit: PublicDomainPictures.net

Our structural biologists work closely with our drug discoverers, exploring how prototype drugs interact with proteins to block signalling pathways. We are particularly keen to focus onhard-to-treat cancer targets, that no current drugs are effective against.

Dr Rob von Montfort, a Team Leader in our Division of Structural Biology, led a recent study that explored how tiny fragment molecules could be used to block a protein called Hsp70 a master controller that oversees several cancer driving signals. Because of its shape, Hsp70 is a challenging target but our research has shown how it might be possible to make drugs that block its action.

Were currently fundraising for a new chromatography machine, which will accelerate our work in structural biology.

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Five reasons we're excited by how structural biology is advancing cancer research - The Institute of Cancer Research (blog)