ArticleProtein science : a publication of the Protein Society2007
The S2 subsites of cathepsins K and L and their contribution to collagen degradation.
Article in Protein science : a publication of the Protein Society, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 55 citations in OpenAlex.
- A Turn-On Fluorescent Amino Acid Sensor Reveals Chloroquine's Effect on Cellular Amino Acids via Inhibiting Cathepsin L.ACS central science · 2023Article
- Structure determinants defining the specificity of papain-like cysteine proteases.Computational and structural biotechnology journal · 2022Review
- Predicting Diagnostic Potential of Cathepsin in Epithelial Ovarian Cancer: A Design Validated by Computational, Biophysical and Electrochemical Data.Biomolecules · 2021Article
- Cathepsin L Inhibitors with Activity against the Liver Fluke Identified From a Focus Library of Quinoxaline 1,4-di-Molecules (Basel, Switzerland) · 2019Article
- Papain-like cysteine proteases prepare plant cyclic peptide precursors for cyclization.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Sequential, but not Concurrent, Incubation of Cathepsin K and L with Type I Collagen Results in Extended Proteolysis.Scientific reports · 2019Article
- Substrate Specificity of Cysteine Proteases Beyond the SFrontiers in molecular biosciences · 2018Article
- Molecular and immunological characterization of cathepsin L-like cysteine protease of Paragonimus pseudoheterotremus.Parasitology research · 2016Article
- The Unusual Resistance of Avian Defensin AvBD7 to Proteolytic Enzymes Preserves Its Antibacterial Activity.PloS one · 2016Article
- Cathepsin L acutely alters microvessel integrity within the neurovascular unit during focal cerebral ischemia.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2015Article
- Dissecting the active site of the collagenolytic cathepsin L3 protease of the invasive stage of Fasciola hepatica.PLoS neglected tropical diseases · 2013Article
- Exhaustive search and solvated interaction energy (SIE) for virtual screening and affinity prediction.Journal of computer-aided molecular design · 2012Article
- Potential role of odanacatib in the treatment of osteoporosis.Clinical interventions in aging · 2012Review
- ECM roles in the function of metabolic tissues.Trends in endocrinology and metabolism: TEM · 2012Review
- Cysteine cathepsins: from structure, function and regulation to new frontiers.Biochimica et biophysica acta · 2012Review
- Biochemical characterization of Plasmodium falciparum dipeptidyl aminopeptidase 1.Molecular and biochemical parasitology · 2011Article
- Cathepsin K inhibitors for osteoporosis and potential off-target effects.Expert opinion on investigational drugs · 2009Review
- Ablation of cathepsin k activity in the young mouse causes hypermineralization of long bone and growth plates.Calcified tissue international · 2009Article
- Structural and functional relationships in the virulence-associated cathepsin L proteases of the parasitic liver fluke, Fasciola hepatica.The Journal of biological chemistry · 2008Article
- Influence of timing (pre-puberty or skeletal maturity) of ovariohysterectomy on mRNA levels in corneal tissues of female rabbits.Molecular vision · 2008Article
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Authors and funding
5 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The exchange of residues 67 and 205 of the S2 pocket of human cysteine cathepsins K and L induces a permutation of their substrate specificity toward fluorogenic peptide substrates. While the cathepsin L-like cathepsin K (Tyr67Leu/Leu205Ala) mutant has a marked preference for Phe, the Leu67Tyr/Ala205Leu cathepsin L variant shows an effective cathepsin K-like preference for Leu and Pro. A similar turnaround of inhibition was observed by using specific inhibitors of cathepsin K [1-(N-Benzyloxycarbonyl-leucyl)-5-(N-Boc-phenylalanyl-leucyl)carbohydrazide] and cathepsin L [N-(4-biphenylacetyl)-S-methylcysteine-(D)-Arg-Phe-beta-phenethylamide]. Molecular modeling studies indicated that mutations alter the character of both S2 and S3 subsites, while docking calculations were consistent with kinetics data. The cathepsin K-like cathepsin L was unable to mimic the collagen-degrading activity of cathepsin K against collagens I and II, DQ-collagens I and IV, and elastin-Congo Red. In summary, double mutations of the S2 pocket of cathepsins K (Y67L/L205A) and L (L67Y/A205L) induce a switch of their enzymatic specificity toward small selective inhibitors and peptidyl substrates, confirming the key role of residues 67 and 205. However, mutations in the S2 subsite pocket of cathepsin L alone without engineering of binding sites to chondroitin sulfate are not sufficient to generate a cathepsin K-like collagenase, emphasizing the pivotal role of the complex formation between glycosaminoglycans and cathepsin K for its unique collagenolytic activity.
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