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Crystal structure of the parasite inhibitor chagasin in complex with papain allows identification of structural requirements for broad reactivity and specificity determinants for target proteases

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Author

  • Izabela Redzynia
  • Anna Ljunggren
  • Anna Bujacz
  • Magnus Abrahamson
  • Mariusz Jaskolski
  • Grzegorz Bujacz

Summary, in English

A complex of chagasin, a protein inhibitor from Trypanosoma cruzi, and papain, a classic family C1 cysteine protease, has been crystallized. Kinetic studies revealed that inactivation of papain by chagasin is very fast (k(on) = 1.5 x 10(6) m(-1).s(-1)), and results in the formation of a very tight, reversible complex (K-i = 36 pm), with similar or better rate and equilibrium constants than those for cathepsins L and B. The high-resolution crystal structure shows an inhibitory wedge comprising three loops, which forms a number of contacts responsible for the high-affinity binding. Comparison with the structure of papain in complex with human cystatin B reveals that, despite entirely different folding, the two inhibitors utilize very similar atomic interactions, leading to essentially identical affinities for the enzyme. Comparisons of the chagasin-papain complex with high-resolution structures of chagasin in complexes with cathepsin L, cathepsin B and falcipain allowed the creation of a consensus map of the structural features that are important for efficient inhibition of papain-like enzymes. The comparisons also revealed a number of unique interactions that can be used to design enzyme-specific inhibitors. As papain exhibits high structural similarity to the catalytic domain of the T. cruzi enzyme cruzipain, the present chagasin-papain complex provides a reliable model of chagasin-cruzipain interactions. Such information, coupled with our identification of specificity-conferring interactions, should be important for the development of drugs for treatment of the devastating Chagas disease caused by this parasite.

Publishing year

2009

Language

English

Pages

793-806

Publication/Series

The FEBS Journal

Volume

276

Issue

3

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Biochemistry and Molecular Biology

Keywords

  • protein
  • papain
  • cysteine proteases
  • Chagas disease
  • cruzipain
  • inhibitors

Status

Published

ISBN/ISSN/Other

  • ISSN: 1742-464X