INHIBITORY CONFORMATION OF THE REACTIVE LOOP OF ALPHA(1)-ANTITRYPSIN

The reactive site loop of the serpin family of serine proteinase inhib itors is flexible and can adopt a number of diverse conformations. A 2 .9 Angstrom resolution structure of alpha(1)-antitrypsin-the principal proteinase inhibitor in human plasma-shows the loop in a stable canon ical conformation matching that found in all other families of serine proteinase inhibitors. This unexpected finding in the absence of loop insertion into the body of the molecule favours a two-stage mechanism of inhibition and provides a model for the heparin activation of antit hrombin. The beta-pleated strand conformation of the loop also account s for the polymerization of the serpins in disease and for their assoc iation with other beta-sheet structures, most notably the beta-amyloid of Alzheimer's disease.