Crystal structure of ovalbumin as a model for the reactive centre of serpins

Abstract

THE serpins are a widely distributed family of proteins with diverse functions; they include the key serine protease inhibitors of human plasma as well as noninhibitory homologues such as hormone-binding globulins, angiotensinogen and egg-white ovalbumin¹. Sequence alignment based on the crystal structure of the cleaved form of the archetypal serpin, a α₁-antitrypsin², indicates that the serpins share a common highly ordered structure³. On cleavage of the reactive centre peptide bond, they characteristically undergo a remarkable conformational change, the newly generated C ter-minus moving some 70 Å to the opposite pole of the molecule. The structure of this post-cleavage form is known, but the conformation of the intact serpins and in particular that of their reactive centre is not. Wright et al.'s structure of plakalbumin⁴ (ovalbumin cleaved by subtilisin) has provided evidence for the conformational change that results from cleavage. We have now determined the structure of native ovalbumin to 1.95 Å resolution and have found that the intact peptide loop forming the analogue to the reactive centre of the inhibitory serpins takes the unexpected form of a protruding, isolated helix. This model of the intact structures of the serpins suggests how they may interact with their target proteases.