Papain-like lysosomal cysteine proteases are processive and digestive enzymes that are expressed in organisms from bacteria to humans. Increasing knowledge about the physiological and pathological roles of cysteine proteases is bringing them into the focus of drug discovery research. These proteases have rather short active-site clefts, comprising three well defined substrate-binding subsites (S2, S1 and S1') and additional broad binding areas (S4, S3, S2' and S3'). The geometry of the active site distinguishes cysteine proteases from other protease classes, such as serine and aspartic proteases, which have six and eight substrate-binding sites respectively. Exopeptidases (cathepsins B, C, H and X), in contrast with endopeptidases (such as cathepsins L, S, V and F), possess structural features that facilitate the binding of N- and C-terminal groups of substrates into the active-site cleft. Other than a clear preference for free chain termini in the case of exopeptidases, the substrate-binding sites exhibit no strict specificities. Instead, their subsite preferences arise more from the specific exclusion of substrate types. This presents a challenge for the design of inhibitors to target a specific cathepsin: only the cumulative effect of an assembly of inhibitor fragments will bring the desired result.
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September 2003
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September 01 2003
Papain-like lysosomal cysteine proteases and their inhibitors: drug discovery targets?
Dŭsan Turk
;
Dŭsan Turk
1
1Department of Biochemistry and Molecular Biology, Jozef Stefan Institute, Jamova 39, Ljubljana, 1000 Slovenia
1To whom correspondence should be addressed (e-mail Dusan.Turk@ijs.si).
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Boris Turk
;
Boris Turk
1Department of Biochemistry and Molecular Biology, Jozef Stefan Institute, Jamova 39, Ljubljana, 1000 Slovenia
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Vito Turk
Vito Turk
1Department of Biochemistry and Molecular Biology, Jozef Stefan Institute, Jamova 39, Ljubljana, 1000 Slovenia
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Biochem Soc Symp (2003) 70: 15–30.
Citation
Jeremy Saklatvala, Hideaki Nagase, Guy Salvesen, Dŭsan Turk, Boris Turk, Vito Turk; Papain-like lysosomal cysteine proteases and their inhibitors: drug discovery targets?. Biochem Soc Symp 1 September 2003; 70 15–30. doi: https://doi.org/10.1042/bss0700015
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