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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

Redzynia, Izabela; Ljunggren, Anna LU ; Bujacz, Anna; Abrahamson, Magnus LU ; Jaskolski, Mariusz and Bujacz, Grzegorz (2009) In The FEBS Journal 276(3). p.793-806
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
protein, papain, cysteine proteases, Chagas disease, cruzipain, inhibitors
in
The FEBS Journal
volume
276
issue
3
pages
793 - 806
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000262468200017
  • scopus:58449086780
ISSN
1742-464X
DOI
10.1111/j.1742-4658.2008.06824.x
language
English
LU publication?
yes
id
05047dd4-173e-42ec-9e7e-3ff268a47a0b (old id 1312653)
date added to LUP
2009-03-13 12:35:27
date last changed
2017-11-19 04:02:05
@article{05047dd4-173e-42ec-9e7e-3ff268a47a0b,
  abstract     = {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.},
  author       = {Redzynia, Izabela and Ljunggren, Anna and Bujacz, Anna and Abrahamson, Magnus and Jaskolski, Mariusz and Bujacz, Grzegorz},
  issn         = {1742-464X},
  keyword      = {protein,papain,cysteine proteases,Chagas disease,cruzipain,inhibitors},
  language     = {eng},
  number       = {3},
  pages        = {793--806},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {The FEBS Journal},
  title        = {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},
  url          = {http://dx.doi.org/10.1111/j.1742-4658.2008.06824.x},
  volume       = {276},
  year         = {2009},
}