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Displacement of the occluding loop by the parasite protein, chagasin, results in efficient inhibition of human cathepsin

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Author

  • Izabela Redzynia
  • Anna Ljunggren
  • Magnus Abrahamson
  • John S. Mort
  • Joanne C. Krupa
  • Mariusz Jaskolski
  • Grzegorz Bujacz

Summary, in English

Cathepsin B is a papain-like cysteine protease showing both endo- and exopeptidase activity, the latter due to a unique occluding loop that restricts access to the active site cleft. To clarify the mode by which natural protein inhibitors manage to overcome this obstacle, we have analyzed the structure and function of cathepsin B in complexes with the Trypanosoma cruzi inhibitor, chagasin. Kinetic analysis revealed that substitution of His-110e, which anchors the loop in occluding position, results in 3-fold increased chagasin affinity (K-i for H110A cathepsin B, 0.35 nM) due to an improved association rate (kon, 5 x 105 M(-1)s(-1)). The structure of chagasin in complex with cathepsin B was solved in two crystal forms (1.8 and 2.67 A resolution), demonstrating that the occluding loop is displaced to allow chagasin binding with its three loops, L4, L2, and L6, spanning the entire active site cleft. The occluding loop is differently displaced in the two structures, indicating a large range of movement and adoption of conformations forced by the inhibitor. The area of contact is slightly larger than in chagasin complexes with the endopeptidase, cathepsin L. However, residues important for high affinity to both enzymes are mainly found in the outer loops L4 and L6 of chagasin. The chagasin- cathepsin B complex provides a structural framework for modeling and design of inhibitors for cruzipain, the parasite cysteine protease and a virulence factor in Chagas disease.

Publishing year

2008

Language

English

Pages

22815-22825

Publication/Series

Journal of Biological Chemistry

Volume

283

Issue

33

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Pharmacology and Toxicology
  • Medicinal Chemistry

Status

Published

Research group

  • Protease Inhibitor Research

ISBN/ISSN/Other

  • ISSN: 1083-351X