The crystal structure of plasminogen activator inhibitor 2 at 2.0 A resolution: implications for serpin function - PubMed (original) (raw)

Comparative Study

. 1999 Jan 15;7(1):43-54.

doi: 10.1016/s0969-2126(99)80008-2.

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Comparative Study

The crystal structure of plasminogen activator inhibitor 2 at 2.0 A resolution: implications for serpin function

S J Harrop et al. Structure. 1999.

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Abstract

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 betasheet 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 A 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 betasheet A (the so-called 'shutter' region) is found to stabilise both the stressed and relaxed forms via a rearrangement of 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 betasheet 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.

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