Crystal structure of an uncleaved serpin reveals the conformation of an inhibitory reactive loop.

The three-dimensional structure of an uncleaved serpin, a variant of human antichymotrypsin engineered to be an inhibitor of human neutrophil elastase, has been determined by X-ray crystallographic methods and is currently being refined at 2.5 A resolution. It contains an intact reactive loop in a distorted helical conformation. A comparison of the current model with that of its cleaved counterpart suggests that the conformational 'stress' of the serpin in its uncleaved and uncomplexed state may not be confined solely to the reactive loop or beta-sheet A. It is intriguing that strand s4A is not pre-inserted into beta-sheet A of the native serpin, and this has profound implications for the mechanism of serpin function.