Altered specificities of genetically engineered α1 antitrypsin variants

S. Jallat, D. Carvallo, L. H. Tessier, D. Roecklin, C. Roitsch, F. Ogushi, Ronald Crystal, M. Courtney

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Seven active site variants of human α1-antitrypsin (α1AT) were produced in Escherichia coli following site-specific mutagenesis of the α1AT complementary DNA. α1AT (Ala 358), α1AT (Ile358 and α1AT (Val358), were efficient inhibitors of both neutrophil and pancreatic elastases, but not of cathepsin G. α1AT (Ala358, Val358) and α1AT (Phe358 specifically inhibited pancreatic elastase and cathepsin G respectively. The most potent inhibitor of neutrophil elastase was α1AT (Leu358), which also proved to be effective against cathepsin G. The α1AT (Arg358) variant inactivated thrombin with kinetics similar to antithrombin III in the presence of heparin. Electrophoretic analysis showed that SDS-stable high mol. wt complexes were formed between the mutant inhibitors and the cognate proteases in each case. These data indicate that effective inhibition occurs when the α1AT P1 residue (position 358) corresponds to the primary specificity of the target protease. Moreover, alteration of the P3 residue (position 356) can further modify the reactivity of the inhibitor. Two of the variants have therapeutic potential: α1AT (Leu358 may be more useful than plasma α1AT in the treatment of destructive lung disorders and α1 (Arg358 could be effective in the control of thrombosis.

Original languageEnglish
Pages (from-to)29-35
Number of pages7
JournalProtein Engineering, Design and Selection
Issue number1
Publication statusPublished - 1 Oct 1986
Externally publishedYes



  • α1-antitrypsin
  • Neutrophil proteases
  • Pulmonary emphysema
  • Thrombin
  • Thrombosis

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biochemistry
  • Molecular Biology

Cite this

Jallat, S., Carvallo, D., Tessier, L. H., Roecklin, D., Roitsch, C., Ogushi, F., Crystal, R., & Courtney, M. (1986). Altered specificities of genetically engineered α1 antitrypsin variants. Protein Engineering, Design and Selection, 1(1), 29-35.