2NQD

Crystal structure of cysteine protease inhibitor, chagasin, in complex with human cathepsin L

2NQD の概要

• エントリーDOI: 10.2210/pdb2nqd/pdb
• 関連するPDBエントリー: 1CS8 1ICF 2H7W 2NNR
• 分子名称: Chagasin, Cathepsin L, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: chagasin-cathepsin l complex, three prong inhibition mode, hydrolase inhibitor-hydrolase complex, hydrolase inhibitor/hydrolase
• 由来する生物種: Trypanosoma cruzi; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36694.87

構造登録者

Redzynia, I.,Bujacz, G.,Ljunggren, A.,Jaskolski, M.,Abrahamson, M. (登録日: 2006-10-31, 公開日: 2007-07-24, 最終更新日: 2024-12-25)

主引用文献

Ljunggren, A.,Redzynia, I.,Alvarez-Fernandez, M.,Abrahamson, M.,Mort, J.S.,Krupa, J.C.,Jaskolski, M.,Bujacz, G.
Crystal structure of the parasite protease inhibitor chagasin in complex with a host target cysteine protease
J.Mol.Biol., 371:137-153, 2007

PubMed 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 (C1 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 A 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 A structure of uncomplexed chagasin, also determined in this study, demonstrates that a conformational change of the first binding loop (L4) 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.

PubMed: 17561110
DOI: 10.1016/j.jmb.2007.05.005

実験手法

X-RAY DIFFRACTION (1.75 Å)