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Protein Engineering vol. 8 no. 1 pp. 45-52, 1995
© 1995 Oxford University Press

RESEARCH-ARTICLE

Highly effective protease inhibitors from variants of human pancreatic secretory trypsin inhibitor (hPSTI): an assessment of 3-D structure-based protein design

M. Szardenings1, B. Vasel2, H.-J. Hecht2, J. Collins3 and D. Schomburg2,4

2Departments of Molecular Structure Research D-38124 Braunschweig, Germany 3Department of Genetics, Gesellschaft for Biotechnologische Forschung D-38124 Braunschweig, Germany

4To whom correspondence should be addressed

The results of a protein design project are used to compare different predictive strategies with respect to proteinprotein interactions. We have been able to generate variants of human pancreatic secretory trypsin inhibitor (hPSTI) optimized with respect to the affinity and specificity for human leukocyte elastase relative to trypsin and chymotrypsin, and in particular chymotrypsin. The extremely strong and specific human leukocyte elastase inhibitors were thus developed in three rounds of mutagenesis and two rounds of 3-D modelling; only 24 variants in total were synthesized, although variations at seven different amino acid positions were involved (i.e. from 207 possible variants). An excellent elastase inhibitor could be designed with the minimum of two amino acid exchanges. The value of structural modelling and actual structure determination is discussed in the light of the experimental results of the designed protein variants and the results of tertiary structure determinations of the free variant and the inhibitorprotease complex. Particular reference is given to the strategy to be followed in protein design projects in general and to the development of protease inhibitors in particular.

Keywords: elastase inhibitors/protease inhibitor/protein design/structure-function relationship

Received February 28, 1994; revised September 22, 1994; accepted September 26, 1994.


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