Background: Plasminogen activator inhibitor 2 (PAI-2) is a member of the serpin family of protease inhibitors that function via a dramatic structural change from a native, stressed state to a relaxed form. This transition is mediated by a segment of the serpin termed the reactive centre loop (RCL); the RCL is cleaved on interaction with the protease and becomes inserted into β sheet A of the serpin. Major questions remain as to what factors facilitate this transition and how they relate to protease inhibition. Results: The crystal structure of a mutant form of human PAI-2 in the stressed state has been determined at 2.0 Å resolution. The RCL is completely disordered in the structure. An examination of polar residues that are highly conserved across all serpins identifies functionally important regions. A buried polar cluster beneath β sheet A (the so-called 'shutter' region) is found to stabilize both the stressed and relaxed forms via a rearrangement hydrogen bonds. Conclusions: A statistical analysis of interstrand interactions indicated that the shutter region can be used to discriminate between inhibitory and non-inhibitory serpins. This analysis implied that insertion of the RCL into β sheet A up to residue P8 is important for protease inhibition and hence the structure of the complex formed between the serpin and the target protease.
Harrop, S. J., Jankova, L., Coles, M., Jardine, D., Whittaker, J. S., Gould, A. R., … Curmi, P. M. G. (1999). The crystal structure of plasminogen activator inhibitor 2 at 2.0 Å resolution: Implications for serpin function. Structure, 7(1), 43–54. https://doi.org/10.1016/S0969-2126(99)80008-2