Advanced

Crystal Structure of the Parasite Protease Inhibitor Chagasin in Complex with a Host Target Cysteine Protease.

Ljunggren, Anna LU ; Redzynia, Izabela; Alvarez Fernandez, Marcia LU ; Abrahamson, Magnus LU ; Mort, John S; Krupa, Joanne C; Jaskolski, Mariusz and Bujacz, Grzegorz (2007) In Journal of Molecular Biology 371(1). p.137-153
Abstract
Chagasin is a protein produced by Trypanosoma cruzi, the parasite that causes Chagas' disease. This small protein belongs to a recently defined family of cysteine protease inhibitors. Although resembling well-known inhibitors like the cystatins in size (110 amino acid residues) and function (they all inhibit papain-like (Cl family) proteases), it has a unique amino acid sequence and structure. We have crystallized and solved the structure of chagasin in complex with the host cysteine protease, cathepsin L, at 1.75 angstrom resolution. An inhibitory wedge composed of three loops (L2, L4, and L6) forms a number of contacts responsible for high-affinity binding (K-i, 39 pM) to the enzyme. All three loops interact with the catalytic groove,... (More)
Chagasin is a protein produced by Trypanosoma cruzi, the parasite that causes Chagas' disease. This small protein belongs to a recently defined family of cysteine protease inhibitors. Although resembling well-known inhibitors like the cystatins in size (110 amino acid residues) and function (they all inhibit papain-like (Cl family) proteases), it has a unique amino acid sequence and structure. We have crystallized and solved the structure of chagasin in complex with the host cysteine protease, cathepsin L, at 1.75 angstrom resolution. An inhibitory wedge composed of three loops (L2, L4, and L6) forms a number of contacts responsible for high-affinity binding (K-i, 39 pM) to the enzyme. All three loops interact with the catalytic groove, with the central loop L2 inserted directly into the catalytic center. Loops L4 and L6 embrace the enzyme molecule from both sides and exhibit distinctly different patterns of protein-protein recognition. Comparison with a 1.7 angstrom structure of uncomplexed chagasin, also determined in this study, demonstrates that a conformational change of the first binding loop (1-4) allows extended binding to the non-primed substrate pockets of the enzyme active site cleft, thereby providing a substantial part of the inhibitory surface. The mode of chagasin binding is generally similar, albeit distinctly different in detail, when compared to those displayed by cystatins and the cysteine protease inhibitory p41 fragment of the invariant chain. The chagasin-cathepsin L complex structure provides details of how the parasite protein inhibits a host enzyme of possible importance in host defense. The high level of structural and functional similarity between cathepsin L and the T cruzi enzyme cruzipain gives clues to how the cysteine protease activity of the parasite can be targeted. This information will aid in the development of synthetic inhibitors for use as potential drugs for the treatment of Chagas disease. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
lysosomal enzymes, Chagas' disease, Trypanosonia critzi, cysteine pepticlases, cysteine proteinases
in
Journal of Molecular Biology
volume
371
issue
1
pages
137 - 153
publisher
Elsevier
external identifiers
  • wos:000248406600012
  • scopus:34447101224
ISSN
1089-8638
DOI
10.1016/j.jmb.2007.05.005
language
English
LU publication?
yes
id
bd6fcb28-82c8-4ad6-8dcd-b0bc8fd65f5b (old id 539868)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17561110&dopt=Abstract
date added to LUP
2007-12-17 10:03:41
date last changed
2017-10-01 04:48:34
@article{bd6fcb28-82c8-4ad6-8dcd-b0bc8fd65f5b,
  abstract     = {Chagasin is a protein produced by Trypanosoma cruzi, the parasite that causes Chagas' disease. This small protein belongs to a recently defined family of cysteine protease inhibitors. Although resembling well-known inhibitors like the cystatins in size (110 amino acid residues) and function (they all inhibit papain-like (Cl family) proteases), it has a unique amino acid sequence and structure. We have crystallized and solved the structure of chagasin in complex with the host cysteine protease, cathepsin L, at 1.75 angstrom resolution. An inhibitory wedge composed of three loops (L2, L4, and L6) forms a number of contacts responsible for high-affinity binding (K-i, 39 pM) to the enzyme. All three loops interact with the catalytic groove, with the central loop L2 inserted directly into the catalytic center. Loops L4 and L6 embrace the enzyme molecule from both sides and exhibit distinctly different patterns of protein-protein recognition. Comparison with a 1.7 angstrom structure of uncomplexed chagasin, also determined in this study, demonstrates that a conformational change of the first binding loop (1-4) allows extended binding to the non-primed substrate pockets of the enzyme active site cleft, thereby providing a substantial part of the inhibitory surface. The mode of chagasin binding is generally similar, albeit distinctly different in detail, when compared to those displayed by cystatins and the cysteine protease inhibitory p41 fragment of the invariant chain. The chagasin-cathepsin L complex structure provides details of how the parasite protein inhibits a host enzyme of possible importance in host defense. The high level of structural and functional similarity between cathepsin L and the T cruzi enzyme cruzipain gives clues to how the cysteine protease activity of the parasite can be targeted. This information will aid in the development of synthetic inhibitors for use as potential drugs for the treatment of Chagas disease.},
  author       = {Ljunggren, Anna and Redzynia, Izabela and Alvarez Fernandez, Marcia and Abrahamson, Magnus and Mort, John S and Krupa, Joanne C and Jaskolski, Mariusz and Bujacz, Grzegorz},
  issn         = {1089-8638},
  keyword      = {lysosomal enzymes,Chagas' disease,Trypanosonia critzi,cysteine pepticlases,cysteine
proteinases},
  language     = {eng},
  number       = {1},
  pages        = {137--153},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Biology},
  title        = {Crystal Structure of the Parasite Protease Inhibitor Chagasin in Complex with a Host Target Cysteine Protease.},
  url          = {http://dx.doi.org/10.1016/j.jmb.2007.05.005},
  volume       = {371},
  year         = {2007},
}