Structure of a serpin-protease complex shows inhibition by deformation

The serpins have evolved to be the predominant family of serine-protease in hibitors in man(1,2). Their unique mechanism of inhibition involves a profo und change in conformation(3), although the nature and significance of this change has been controversial. Here we report the crystallographic structu re of a typical serpin-protease complex and show the mechanism of inhibitio n. The conformational change is initiated by reaction of the active serine of the protease with the reactive centre of the serpin. This cleaves the re active centre, which then moves 71 Angstrom to the opposite pole of the ser pin, taking the tethered protease with it. The tight linkage of the two mol ecules and resulting overlap of their structures does not affect the hypers table serpin, but causes a surprising 37% loss of structure in the protease . This is induced by the plucking of the serine from its active site, toget her with breakage of interactions formed during zymogen activation(4). The disruption of the catalytic site prevents the release of the protease from the complex, and the structural disorder allows its proteolytic destruction (5,6). It is this ability of the conformational mechanism to crush as well as inhibit proteases that provides the serpins with their selective advanta ge.