2O6X

Crystal Structure of ProCathepsin L1 from Fasciola hepatica

2O6X の概要

• エントリーDOI: 10.2210/pdb2o6x/pdb
• 関連するPDBエントリー: 1CJL
• 分子名称: Secreted cathepsin L 1 (2 entities in total)
• 機能のキーワード: hydrolase; thiol protease; cysteine protease; zymogen, hydrolase
• 由来する生物種: Fasciola hepatica (liver fluke)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35109.12

構造登録者

Brinen, L.S.,Dalton, J.P.,Geiger, S.,Marion, R.,Stack, C.M. (登録日: 2006-12-08, 公開日: 2007-12-18, 最終更新日: 2024-11-20)

主引用文献

Stack, C.M.,Caffrey, C.R.,Donnelly, S.M.,Seshaadri, A.,Lowther, J.,Tort, J.F.,Collins, P.R.,Robinson, M.W.,Xu, W.,McKerrow, J.H.,Craik, C.S.,Geiger, S.R.,Marion, R.,Brinen, L.S.,Dalton, J.P.
Structural and functional relationships in the virulence-associated cathepsin L proteases of the parasitic liver fluke, Fasciola hepatica.
J.Biol.Chem., 283:9896-9908, 2008

PubMed Abstract: The helminth parasite Fasciola hepatica secretes cysteine proteases to facilitate tissue invasion, migration, and development within the mammalian host. The major proteases cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) were recombinantly produced and biochemically characterized. By using site-directed mutagenesis, we show that residues at position 67 and 205, which lie within the S2 pocket of the active site, are critical in determining the substrate and inhibitor specificity. FheCL1 exhibits a broader specificity and a higher substrate turnover rate compared with FheCL2. However, FheCL2 can efficiently cleave substrates with a Pro in the P2 position and degrade collagen within the triple helices at physiological pH, an activity that among cysteine proteases has only been reported for human cathepsin K. The 1.4-A three-dimensional structure of the FheCL1 was determined by x-ray crystallography, and the three-dimensional structure of FheCL2 was constructed via homology-based modeling. Analysis and comparison of these structures and our biochemical data with those of human cathepsins L and K provided an interpretation of the substrate-recognition mechanisms of these major parasite proteases. Furthermore, our studies suggest that a configuration involving residue 67 and the "gatekeeper" residues 157 and 158 situated at the entrance of the active site pocket create a topology that endows FheCL2 with its unusual collagenolytic activity. The emergence of a specialized collagenolytic function in Fasciola likely contributes to the success of this tissue-invasive parasite.

PubMed: 18160404
DOI: 10.1074/jbc.M708521200

実験手法

X-RAY DIFFRACTION (1.4 Å)