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.