Solution Structure and Backbone Dynamics of the Trypanosoma cruzi Cysteine Protease Inhibitor Chagasin

Salmon, Didier; Aido-Machado, Rodolpho do; Diehl, Anne; Leidert, Martina; Schmetzer, Oliver; Lima, Ana Paula; Scharfstein, Júlio; Oschkinat, Hartmut; Pires, Juliana Rico

doi:10.1016/j.jmb.2006.01.064

Cited by 36 publications

(40 citation statements)

References 36 publications

(46 reference statements)

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“…Although the general fold of the chagasin molecule determined in this study is the same as that derived from solution NMR measurements (PDB code 2FO8), 14 the r.m.s. deviation in Cα superposition with the first chain of the NMR ensemble is very high, approaching 3 Å (Table 3).…”

Section: Comparison With the Nmr Modelmentioning

confidence: 86%

“…12 Early molecular modeling studies predicted an immunoglobulin-like fold for chagasin, 13 which was essentially confirmed by a recent NMR study 14 and an X-ray analysis of chagasin crystallized in the presence of polyethylene glycol (PEG). 15 Despite this progress in the elucidation of the chagasin structure, the key issue of the mechanism of inhibition has been left to conjecture, based only on modeling 15,16 and cursory NMR data 14 .…”

Section: 9mentioning

confidence: 91%

“…Although the structures of T. cruzi chagasin and of its Leishmania mexicana homologue have been reported recently, 14,15,16 a brief overview of our high-resolution crystal structure of free chagasin is useful. The chagasin molecule is composed almost exclusively of β-strands (Fig.…”

Section: Description Of the Chagasin Structurementioning

confidence: 99%

“…Two recently published studies 14,15 ethanolamine, pH 9.0, using a gradient of the same buffer containing 1M NaCl for elution. Purity of the recombinant chagasin was verified by SDS-PAGE (4-12%; Novex; Invitrogen AB, Stockholm, Sweden) and 1% agarose gel electrophoresis.…”

Section: Models Of Chagasin Binding Modementioning

confidence: 99%

See 3 more Smart Citations

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

Ljunggren

Redzynia

Alvarez-Fernandez

et al. 2007

Journal of Molecular Biology

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The residues of the inhibitor are labeled without a chain designator. The residues of the enzyme are marked "e", except for the first residue, marked "p" (E1p), which belongs to the prosegment sequence.Abbreviations used: E-64, L-trans-epoxysuccinylleucylamido-(4-guanidino)butane; MAD, multiwavelength anomalous diffraction; MS, mass spectrometry; PDB, Protein Data Bank; NHMec, 7-(4-methyl)coumarylamide; r.m.s., root mean square; Z-, carboxybenzoyl-; GST, glutathione-S-transferaseChagasin-cathepsin L complex structure 3 SUMMARY

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Section: Comparison With the Nmr Modelmentioning

confidence: 86%

Section: 9mentioning

confidence: 91%

Section: Description Of the Chagasin Structurementioning

confidence: 99%

Section: Models Of Chagasin Binding Modementioning

confidence: 99%

See 2 more Smart Citations

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

Ljunggren

Redzynia

Alvarez-Fernandez

et al. 2007

Journal of Molecular Biology

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“…The properties of chagasin are similar to those of cystatins, but its structure is very different (15)(16)(17). Chagasin belongs to a new inhibitor family (MEROPS family I42) (1) and its mode of binding to the cysteine endopeptidases, cathepsin L and falcipain, has been recently elucidated (16,18,19).…”

mentioning

confidence: 99%

Displacement of the Occluding Loop by the Parasite Protein, Chagasin, Results in Efficient Inhibition of Human Cathepsin B

Redzynia

Ljunggren

Abrahamson

et al. 2008

Journal of Biological Chemistry

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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 (k on , 5 ؋ 10 5 M ؊1 s ؊1 ). The structure of chagasin in complex with cathepsin B was solved in two crystal forms (1.8 and 2.67 Å 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.

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Roles of Naturally Occurring Protease Inhibitors in the Modulation of Host Cell Signaling and Cellular Invasion by Trypanosoma cruzi

Scharfstein

Lima

Subcellular Biochemistry

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Solution Structure and Backbone Dynamics of the Trypanosoma cruzi Cysteine Protease Inhibitor Chagasin

Cited by 36 publications

References 36 publications

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

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

Displacement of the Occluding Loop by the Parasite Protein, Chagasin, Results in Efficient Inhibition of Human Cathepsin B

Roles of Naturally Occurring Protease Inhibitors in the Modulation of Host Cell Signaling and Cellular Invasion by Trypanosoma cruzi

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