Virtuelle (Nano) Welten: PDB Molecule of the Month 53: Serpins

Tripping the Trap

The flexible loop of serpins, known as the reactive center loop, is the bait and trap. The protease, shown here in green, binds to the bait and begins to perform its normal cleavage reaction. The structure on the left, from PDB entry 1k9o, shows trypsin just after it binds. The reactive serine in the protease attacks the loop, forms a bond with the chain, and makes the break. Normally, a water molecule would then be used to release the protease from its target. But instead, the serpin takes control before the unlucky trypsin can extricate itself. The flexible loop, now cleaved and free to move, zips into a comfortable groove in the side of the serpin, dragging the protease all the way to the other side, as shown in the structure on the right, from PDB entry 1ezx. You might think that the trypsin could then perform the rest of its reaction and release itself. But the strand of the serpin, now gripped firmly in the groove on its side, is just a few amino acids too short, so the trypsin is jammed up against the bottom of the serpin. This pulls the active site of trypsin out of shape, so that it is no longer active. It also destabilizes the trypsin, so that it partially unfolds. This makes it an easy target for the cellular machinery that cleans up defective proteins, which destroys both the protease and the one-shot serpin.