title: The crystal structure of plasminogen activator inhibitor 2 at 2.0 A resolution: implications for serpin function.
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.
authors.affiliation: Initiative in Biomolecular Structure, School of Physics, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Harrop
authors.forename: L
authors.initials: L
authors.lastname: Jankova
authors.forename: M
authors.initials: M
authors.lastname: Coles
authors.forename: D
authors.initials: D
authors.lastname: Jardine
authors.forename: J S
authors.initials: JS
authors.lastname: Whittaker
authors.forename: A R
authors.initials: AR
authors.lastname: Gould
authors.forename: A
authors.initials: A
authors.lastname: Meister
authors.forename: G C
authors.initials: GC
authors.lastname: King
authors.forename: B C
authors.initials: BC
authors.lastname: Mabbutt
authors.forename: P M
authors.initials: PM
authors.lastname: Curmi
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017396:Plasminogen Activator Inhibitor 2 / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D015843:Serpins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D017396:Plasminogen Activator Inhibitor 2; D011994:Recombinant Proteins; D015843:Serpins