Tags

Type your tag names separated by a space and hit enter

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.
FEBS J. 2009 Feb; 276(3):793-806.FJ

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) x 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.

Links

Aggregator Full Text

Authors+Show Affiliations

Redzynia I
Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Technical University of Lodz, Poland.
Ljunggren A
No affiliation info available
Bujacz A
No affiliation info available
Abrahamson M
No affiliation info available
Jaskolski M
No affiliation info available
Bujacz G
No affiliation info available

MeSH

Amino Acid SequenceAnimalsCrystallography, X-RayCysteine EndopeptidasesCysteine Proteinase InhibitorsEnzyme ActivationModels, MolecularPapainProtein BindingProtein Structure, QuaternaryProtozoan ProteinsSequence AlignmentSubstrate SpecificityTrypanosoma cruzi

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19143838

Citation

Redzynia, Izabela, et al. "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." The FEBS Journal, vol. 276, no. 3, 2009, pp. 793-806.
Redzynia I, Ljunggren A, Bujacz A, et al. 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. FEBS J. 2009;276(3):793-806.
Redzynia, I., Ljunggren, A., Bujacz, A., Abrahamson, M., Jaskolski, M., & Bujacz, G. (2009). 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. The FEBS Journal, 276(3), 793-806. https://doi.org/10.1111/j.1742-4658.2008.06824.x
Redzynia I, et al. 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. FEBS J. 2009;276(3):793-806. PubMed PMID: 19143838.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Redzynia,Izabela, AU - Ljunggren,Anna, AU - Bujacz,Anna, AU - Abrahamson,Magnus, AU - Jaskolski,Mariusz, AU - Bujacz,Grzegorz, PY - 2009/1/16/entrez PY - 2009/1/16/pubmed PY - 2009/2/12/medline SP - 793 EP - 806 JF - The FEBS journal JO - FEBS J VL - 276 IS - 3 N2 - 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) x 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. SN - 1742-4658 UR - https://www.unboundmedicine.com/medline/citation/19143838/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_ L2 - https://doi.org/10.1111/j.1742-4658.2008.06824.x DB - PRIME DP - Unbound Medicine ER -