‘This switches the lights on’ – how discovering the shape of three proteins could lead to new cancer drugs - Cancer Research UK

The ‘lightbulb moment’ is a much-coveted event in a scientist’s career.

But in reality, it’s something more likely to appear in a work of fiction than in the confines of the laboratory. Evidence grows with steady, incremental progress – rather than with screams of ‘Eureka’!

But the results of a new US study are a bit different, turning the lights on for researchers who have spent the last two decades studying a particular group of molecules.

The three proteins, called hypoxia-inducible factors, or HIFs for short, are activated by our cells when oxygen is scarce in our tissues.

These proteins join together in two unique combinations, to switch on genes that control how cells behave.

And in cancer they offer a complex escape mechanism that allows tumour cells to adapt to low-oxygen conditions and keep growing.

Because of this crucial role in cancer cell growth, scientists around the world have been searching for ways to interfere with how the HIFs work. But much like trying to design a key without seeing the lock, this goal has been tough – because nobody knew what shape the proteins were.

Now that has changed.

Publishing their findings in the journal Nature, the US team has uncovered the precise shape of the HIF proteins. And, crucially, their atomic level snaps reveal five spots on the proteins that the researchers believe could be promising targets for new drugs.

Working in the dark

“We’ve known about the HIFs since the early 90s,” explains Professor Ali Tavassoli, a Cancer Research UK scientist whose team works on developing molecules that target the HIF proteins.

“It‘s been clear for a long time that HIFs could play an important role in how cancer cells grow.” As a tumour develops, it outgrows its blood supply and becomes starved of oxygen. But the HIFs help cancer cells adapt to these tough conditions in the body where healthy cells would normally die. The genes that are switched on by the HIFs boost the amount of oxygen and nutrients delivered to the tumour by encouraging the growth of new blood vessels.

The three proteins – called the HIF-1α, HIF-2α and HIF-1β subunits – work in pairs, sticking to DNA and switching on genes. And the pairs are always made up of one of the alpha subunits stuck to HIF-1β.

“The most promising way to switch off HIF is to prevent the two subunits from sticking together and forming a functional pair,” says Ali.

Protein crystals. Flickr/CC-BY-NC-SA 2.0

“But so far we’ve all been working in the dark, using clever techniques to produce and test lots of potential drugs, but with no way of refining them, as we had no idea of what the complete HIF pair looks like.”

The new study changes all this. For the first time, researchers now have a clear picture of the complete pair.

To do this they produced highly purified forms of the proteins, and captured the HIF pairs in crystals. Once the team had the crystals, they were able to shine X-rays on them and collect information about the shape of the proteins based on how the beams bend when they hit the crystal – a technique called X-ray crystallography.

This type of protein shape analysis is vital for refining how scientists design and develop new drugs.

And according to Professor Fraydoon Rastinejad, an author on the study from the Sanford Burnham Prebys Medical Discovery Institute in the US, the discovery should help researchers understand how drugs might stick to HIF pairs.

And this is something Ali is particularly excited about.

Switching the lights on

“This paper is a game changer as it finally switches the lights on,” he says.

The shape of HIF (HIF-2α in purple, HIF-1β in green and DNA in orange). © Wu et al (2015) Nature

“We now know what HIF looks like. And what’s amazing is, it’s not what you’d expect.”

Looking at the two subunits individually they appear similar, they have symmetry. But the latest snapshots show that when the proteins stick together they do so in an unsymmetrical way.

“HIF-1β wraps around HIF-1α,” says Ali, “and this isn’t what we would have expected.”

“Other researchers have managed to capture the shape of a particular bit of the protein before. But it turns out that the shape the complete pair forms is not the same.”

And this is where the new study opens up important opportunities for future work.

With the mystery of HIF’s shape solved, the US team now plans to start looking for how faults (mutations) in the DNA ‘recipe’ for the HIFs might change how the protein looks.

“Our next step is to analyse a large number of patient samples with mutations in HIF proteins,” says Rastinejad. If the faults change the shape of the proteins they may make them stickier, which could help the HIFs switch on genes and keep cancer cells growing.

Accelerating efforts

The new snapshots of HIF also reveal some promising areas of the protein where drug molecules could be targeted to. And it’s this finding that will help researchers working on developing HIF drugs.

“Back in 2013, my team discovered a compound that specifically stops the HIF-1 proteins pairing up,” explains Ali.

“We’ve been working on developing it ever since, including trying to find where the drug sticks to HIF – something we can now do thanks to this latest study.”

“This new finding will significantly accelerate ours, and others’, efforts in developing HIF-targeting drugs that could be one day become real treatments.”

The lights are on now, and we can’t wait to see what ideas appear next.

Nick

Image