The shape of things to come?

Over the years, scientists looking inside our cells have found that hundreds of different proteins play a role in the development of cancer.

Some of these have a walk-on part. Others are virtually extras. But there are some that can be thought of as the big “stars” of the field – the George Clooney or Nicole Kidman of cell division, if you like. One of these is called p53, and often billed as “the guardian of the genome.”

But despite years of research, we’re still a long way from knowing exactly how p53 ‘works’. A paper published last week, in top science journal PNAS, is helping change all that. Researchers are working out the protein’s exact 3D structure, and aim to use this knowledge to find out more about this reclusive superstar, and what makes it tick…

Scientists have been fascinated by p53 since its discovery in 1979 – thanks in part to top Cancer Research UK scientist Professor Sir David Lane, who helped to track it down.

It seems that, in healthy cells, p53 plays the role of a detective, tracking down DNA damage. If it finds any, it springs into action, kicking off a cascade of events which can either halt the cell’s ability to divide, or even cause it to commit suicide. This appears to be one of evolution’s most important anti-cancer mechanisms, protecting us from the disease by neutralising potentially dodgy cells.

And one of the most exciting findings in recent cancer research was that p53 is faulty in the majority of human cancers. This failure allows cancer cells, which are riddled with DNA damage that p53 would normally spot, to cheat death and multiply out of control.

So scientists think that if we could develop treatments based on reactivating p53, this might be a good way to treat most cases of cancer. But so far this has proved impossible to achieve, partly because we have a relatively limited understanding of the exact way p53 recognises damage and alerts the rest of the cell.

Last week, scientists came a little closer to understanding this mysterious molecule after an international collaboration of researchers managed to figure out p53’s 3-D structure, and see exactly how it sticks to DNA.

The team was led by Professor Sir Alan Fersht at the University of Cambridge, and you can see a representation of the fruits of their labour in the picture below. Certain important parts of p53 are coloured red, green and blue while DNA is a rather fetching shade of purple.

Now this may not sound terribly exciting – unless you’re a structural biologist, of course – but it has taken many years, and much frustration, to get to this point. Despite figuring out the structure of small parts of p53, one at a time, no-one has been able to work out the whole shape of the molecule – until now.

Previous efforts have been hampered by the fact that the protein is quite unstable and tends to break down or fall apart easily. And there are quite a few parts of the protein (shown in grey in the pic) that are “disordered”, meaning that they don’t seem to take on particular shape at all.

The new structure contains no startling revelations – science generally doesn’t work like that – but it represents another important step on the road to understanding this molecular superstar.

So what does this actually mean for cancer research? Increasingly, potential new cancer treatments are being discovered using computer programmes that can “design” drugs to fit into the molecular structures of important molecules involved in cancer.

So understanding more about the shape of p53 might help scientists to design drugs that can switch it on in cancer cells, or mimic its function in triggering cell death. All this is still a long way off in the future, but this discovery has brought us one step closer.

You can read the abstract of this research paper online.