From the lab.

How we measure whether a bridge forms

A degrader only works if it holds two proteins at once: the problem protein and a ligase, the enzyme that tags it. Scientists call the three together a ternary complex. Before anything else, we check that it forms.

First, in a test tube. We label the two proteins with a pair of fluorescent markers. When the degrader brings them close, energy passes from one marker to the other without any light passing between them, and the second marker glows. An instrument reads that glow. This kind of test is called TR‑FRET: the first marker glows for a long time, so the reading is taken after a short delay, which cuts out background light. No glow means no bridge.

Then, in cells. We attach a tiny tag (HiBiT) to the problem protein inside living cells. With its partner piece (LgBiT) it gives off light, so the glow shows how much of the protein is there. Then we add the degrader. If the bridge forms and the cell’s shredder does its work, the glow fades as the protein is taken apart. We record how much of the degrader it takes to clear half the protein, and how much protein is left at the end.

A molecule that forms a strong bridge in the tube but clears little in cells tells us something too: sometimes the angle between the two proteins is wrong, so the tags cannot reach, or the molecule cannot get into cells.

A new lab opens in Cambridge

Our new lab in Cambridge is close to the hospitals and universities we work with. It has room for 40 scientists and a cell biology floor where degraders are tested in living cells.

It brings our chemists and biologists under one roof. Until now, samples travelled between London and Cambridge.

We are hiring for the new lab. See our open roles.

A beginner’s guide to the proteasome

Every cell has a shredder for proteins it no longer needs. It is called the proteasome, and a single cell holds many thousands of them.

It is shaped like a barrel. The cutting happens inside the core, out of harm’s way. A cap on one or both ends decides what gets in: it reads a tag made of a small protein called ubiquitin. A chain of at least four ubiquitins usually means “take this apart”.

The cap unfolds the protein and threads it into the barrel like a ribbon. Inside, it is cut into short pieces that the cell can reuse to build new proteins. The ubiquitin tags are taken off at the door and used again.

Degraders do not change the shredder at all. They put the tag on a protein the cell would otherwise keep, by holding it next to a ligase until the tags are added. The structure in our pictures is the human 26S proteasome, PDB 5GJR, from a published study.