Every cancer drug is a molecule – a collection of atoms put together in a particular shape. Modern drugs are meticulously designed with a particular target in mind, either within a cancer cell or on its surface.

These targets are proteins, the drivers of all our biological processes, which are co-opted in cancer to drive cell growth and spread.

Our structural biologists explore the shapes of these proteins in detail, down to the individual atom, and work out how they interlock with other proteins and potential drugs.

As Laura Mariotti, a PhD student in the ICR’s Division of Structural Biology, explains: “We’re 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 chemists might be able to design drugs that turn the protein on or off.”

To do this, researchers use two main techniques: protein X-ray crystallography and electron microscopy “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,” Laura explains. “Then we irradiate the crystal with X-rays to create a map of the atoms’ positions.

“In electron microscopy, we image our protein at around 50,000 times magnification using a beam of electrons, rather than light.” This enables structural biologists to make two-dimensional projections of protein shapes in many orientations, and use these different views to re-construct a model of the 3D object.

Making maps

Several ICR-led research programmes are using these two techniques to improve our knowledge of key cancer-causing proteins, and are sharing their discoveries with the whole field.

One focus is cell division – normally a highly regulated process, but hijacked by cancer to drive its continued growth. Recent studies from the ICR’s Division of Structural Biology have produced detailed maps of two major players in this process: the proteasome and the anaphasepromoting 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.

 

Drug discovery

Our structural biologists also work closely with our drug discoverers, exploring how prototype drugs interact with proteins to block signalling pathways. They often focus on cancer targets that no current drugs are effective against.

For example, Dr Rob von Montfort 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 cancerdriving 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.

Cool tech

Some of our researchers are also using a developing technology that is sparking much excitement in the field, called cryo-electron microscopy.

This involves freezing and imaging samples at -180°C to preserve the finest details of the protein shapes.

Dr Ed Morris’s team used the technique to image the proteasome, a protein complex important for cell division and protein degradation, at ultra-low temperatures. The team revealed a target site for potential drugs – and even showed an inhibitor molecule bound in place, blocking the protein’s action.

Dr Morris says: “Cryo-electron 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.”

Our structural biologists are helping to answer some of the big unknown questions in biology – as well as helping to discover new treatments for cancer.

Structural biology: a new scientific frontier

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