The structure of active serpin 1K from Manduca sexta

Background: The reactive center loops (RCL) of serpins undergo large confor mational changes triggered by the interaction with their target protease. A vailable crystallographic data suggest that the serpin RCL is polymorphic, but the relevance of the observed conformations to the competent active str ucture and the conformational changes that occur on binding target protease has remained obscure. New high-resolution data on an active serpin, serpin 1K from the moth hornworm Manduca sexta, provide insights into how active serpins are stabilized and how conformational changes are induced by protea se binding. Results: The 2.1 Angstrom structure shows that the RCL of serpin 1 K, like that of active alpha(1)-antitrypsin, is canonical, complimentary and ready to bind to the target protease between P-3 and P-3' (where P refers to stan dard protease nomenclature). In the hinge region (P-17-P-13), however, the RCL of serpin 1 K, like ovalbumin and alpha(1)-antichymotrypsin, forms tigh t interactions that stabilize the five-stranded closed form of beta sheet A . These interactions are not present in, and are not compatible with, the o bserved structure of active alpha(1)-antitrypsin. Conclusions: Serpin 1K may represent the best resting conformation for serp ins - canonical near P-1, but stabilized in the closed conformation of beta sheet A. By comparison with other active serpins, especially alpha(1)-anti trypsin, a model is proposed in which interaction with the target protease near P-1 leads to conformational changes in beta sheet A of the serpin.