Transcript: Protein crystallography

Ever tried doing a jigsaw puzzle with your eyes closed? In some ways, that’s what designing a new medicine is like – or that’s how it used to be.

Biochemists like us can now use tiny crystals to actually see what we are doing when we are designing new drugs.

Hi, I’m Janet Newman.

And I’m Tom Peat.

And we’re going to show you how it’s done.

Most medicines work by binding to a certain protein in the body that’s responsible for causing disease, and stopping that protein from working. Now, in the past finding a chemical that would bind to and inhibit these types of proteins – disease-causing proteins – was very tricky, largely because chemists didn’t know what shape the chemical had to be in order to fit into the protein molecule, because they had no way of seeing the space in the protein where the chemical would need to bind. Just imagine having millions of keys but not being able to choose the right one for a lock because you haven’t seen the keyhole.

Today, however, biochemists have a technique to help them see the structure of the protein that they’re looking at. This technique is called X-ray crystallography.

What’s crystallography? Well, it involves shining light through a crystal and examining how it scatters, to determine the structure of the crystal right down to the level of its atoms.

Before we can use crystallography to determine the structure of a protein, we have to coax our protein into crystals. This is done with the help of a robot which mixes nano-droplets of the protein solution with a solvent. Then we leave the protein droplets at a certain temperature in a machine called a ‘hotel’ until they crystallise.

How long does it take a protein to crystallise? Well, sometimes minutes and sometimes years. But we know when it’s happened by looking at magnified images of the experiments which get captured while they’re inside.

Once we’re done actually making the protein crystals, what we will do is bind chemical fragments to those protein crystals.

This is done by soaking the protein crystals in solutions containing the fragments. Then we find if any of the fragments have bound to the protein, using X-ray crystallography.

A beam of X-rays is directed through the crystallised protein, which causes those X-rays to scatter. The scattering pattern tells us about the crystal’s structure and, after some calculations, allows us to come up with a sort of image of the protein’s binding site.

We can now look at these images and see how chemical fragments actually bind in the binding site of the protein.

We use this information to actually tailor-make molecules that bind better to the protein in this binding site.

After we’ve some up with chemicals that can do the job we want them to do, these can go on to be tested to see if they’ll make safe and effective medicines.

And that’s how we use crystals – tiny protein crystals – to help us discover new medicines.