3E1Z

Crystal structure of the parasite protesase inhibitor chagasin in complex with papain

Summary for 3E1Z

• Entry DOI: 10.2210/pdb3e1z/pdb
• Related: 1KHQ 1ME3 2NQD 2OUL 3CBJ 3CBK
• Descriptor: Chagasin, Papain, ZINC ION, ... (6 entities in total)
• Functional Keywords: chagasin-papain complex, papain, chagas disease, cysteine proteinases, protein inhibitors, cytoplasmic vesicle, protease inhibitor, thiol protease inhibitor, allergen, hydrolase, protease, thiol protease, zymogen, hydrolase inhibitor-hydrolase complex, hydrolase inhibitor/hydrolase
• Biological source: Trypanosoma cruzi; More
• Cellular location: Flagellar pocket: Q966X9
• Total number of polymer chains: 2
• Total formula weight: 36092.49

Authors

Redzynia, I.,Bujacz, G.,Bujacz, A.,Ljunggren, A.,Abrahamson, M.,Jaskolski, M. (deposition date: 2008-08-05, release date: 2009-01-27, Last modification date: 2024-11-06)

Primary citation

Redzynia, I.,Ljunggren, A.,Bujacz, A.,Abrahamson, M.,Jaskolski, M.,Bujacz, G.
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., 276:793-806, 2009

PubMed 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.

PubMed: 19143838
DOI: 10.1111/j.1742-4658.2008.06824.x

Experimental method

X-RAY DIFFRACTION (1.86 Å)