Inhibitory conformation of the reactive loop of alpha 1-antitrypsin

Nat Struct Biol. 1996 Aug;3(8):676-81. doi: 10.1038/nsb0896-676.


The reactive site loop of the serpin family of serine proteinase inhibitors is flexible and can adopt a number of diverse conformations. A 2.9 A resolution structure of alpha 1-antitrypsin-the principal proteinase inhibitor in human plasma-shows the loop in a stable canonical conformation matching that found in all other families of serine proteinase inhibitors. This unexpected finding in the absence of loop insertion into the body of the molecule favours a two-stage mechanism of inhibition and provides a model for the heparin activation of antithrombin. The beta-pleated strand conformation of the loop also accounts for the polymerization of the serpins in disease and for their association with other beta-sheet structures, most notably the beta-amyloid of Alzheimer's disease.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Heparin / pharmacology
  • Humans
  • Liver Cirrhosis / etiology
  • Models, Molecular
  • Mutation
  • Polymers
  • Protein Conformation
  • Structure-Activity Relationship
  • alpha 1-Antitrypsin / chemistry*
  • alpha 1-Antitrypsin / drug effects
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / ultrastructure


  • Polymers
  • alpha 1-Antitrypsin
  • Heparin