Structural basis for reversible and irreversible inhibition of human cathepsin L by their respective dipeptidyl glyoxal and diazomethylketone inhibitors

Shenoy, Rajesh T.; Sivaraman, J.

doi:10.1016/j.jsb.2010.09.007

Cited by 30 publications

(33 citation statements)

References 33 publications

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“…In a seminal study, Choe et al studied substrate specificity using a highly diversified positional scanning synthetic combinatorial library comprised of 160,000 fluorogenic tetrapeptides; this allowed to differentiate individual enzymes binding propensity based on their distinct amino acid preferences [93]. By capitalizing on this strategy, they successfully developed a selective substrate and substrate-based inhibitor of cathepsin K. The other important contribution to our understanding of subsite binding preferences of cathepsin L enzyme stems from several timely crystal structure studies that helped reveal key difference in the structural landscape of enzyme subsites [94][95][96]. In an important study, Shenoy et al solved the crystal structure of ligand bound cathepsin L and documented the structural compositions of ligand binding sites ( Figure 4) [96].…”

Section: Inhibitory Ligand Inhibition Constant (K I )mentioning

confidence: 99%

“…By capitalizing on this strategy, they successfully developed a selective substrate and substrate-based inhibitor of cathepsin K. The other important contribution to our understanding of subsite binding preferences of cathepsin L enzyme stems from several timely crystal structure studies that helped reveal key difference in the structural landscape of enzyme subsites [94][95][96]. In an important study, Shenoy et al solved the crystal structure of ligand bound cathepsin L and documented the structural compositions of ligand binding sites ( Figure 4) [96]. Their analysis of Z-Phe-Tyr (O-tert-Butyl)-C(O)C(H)O bound cathepsin L revealed that (a) S1 subsite is relatively wide and unrestricted and composed of Asp162, Ser24, and Cys25, (b) S1 subsite is guided by Leu144, Trp189, Ala138 and Gly139 where Trp189 associates with Trp193 and Phe143 and forms an aromatic cluster that accommodates the tert-butyl group (c) side chains of Leu69 and Met70 help form the S2 subsite that engages in non-polar interactions with the phenyl side chain, and finally, (d) the carboxybenzyl group finds interaction with the Gly68 residue of S3 subsite (Figure 4).…”

Section: Inhibitory Ligand Inhibition Constant (K I )mentioning

confidence: 99%

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A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

Dana

Pathak

2020

Molecules

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Human cathepsin L belongs to the cathepsin family of proteolytic enzymes with primarily an endopeptidase activity. Although its primary functions were originally thought to be only of a housekeeping enzyme that degraded intracellular and endocytosed proteins in lysosome, numerous recent studies suggest that it plays many critical and specific roles in diverse cellular settings. Not surprisingly, the dysregulated function of cathepsin L has manifested itself in several human diseases, making it an attractive target for drug development. Unfortunately, several redundant and isoform-specific functions have recently emerged, adding complexities to the drug discovery process. To address this, a series of chemical biology tools have been developed that helped define cathepsin L biology with exquisite precision in specific cellular contexts. This review elaborates on the recently developed small molecule inhibitors and probes of human cathepsin L, outlining their mechanisms of action, and describing their potential utilities in dissecting unknown function.Molecules 2020, 25, 698 2 of 41 also now well established and has been a subject of elegant reviews elsewhere [25][26][27]. Unfortunately, several overlapping and redundant functions of cathepsin L have also emerged [5,[28][29][30]. It is therefore critically important that its functional biology in both normal and disease-specific cell types be clearly annotated before significant resources are directed in drug discovery endeavors. In this review, we will briefly outline the biogenesis of cathepsin L, describe its post-translational processing and trafficking, and highlight key structural features required for formation of an active and mature cathepsin L. A brief summary of cathepsin L biology and its role in human diseases is provided next. Finally, a detailed and up-to-date report on existing cathepsin L-targeting small molecule inhibitors and functional probes with their mechanistic details is described.Human cathepsin L gene, CTHL (Uniprot primary accession number: P07711), located at the 9q21-q22 position of chromosome 9, encodes for a total of 333 amino acid peptide sequence (M.W. = 37,564 kDa) [31]. The coding space includes the regions of a N-terminal signal peptide, two pro-peptides, and two mature peptides comprising of a heavy (H) chain and a light (L) chain ( Figure 1). After transcription, the signal peptide is co-translationally removed in polysome and the resulting 41 kDa pro-cathepsin L is translocated to endoplasmic reticulum where it undergoes N-linked glycosylation with mannose rich sugars. The mannose sugars on the pro-cathepsin L are then phosphorylated in cis Golgi by UDP-N-acetylglucosamine:N-acetylglucosaminephosphotransferase enzyme [32]. The mannose-6-phosphate (M6P) receptors located on the surface of the trans Golgi network recognize the M6P-pro-cathepsin peptide and deliver the pro-cathepsin L peptide to the lysosome via the endolysosomal pathway. The weakly acidic environment of endosome/lysosome releases M6P receptors and the phosphate ...

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Section: Inhibitory Ligand Inhibition Constant (K I )mentioning

confidence: 99%

Section: Inhibitory Ligand Inhibition Constant (K I )mentioning

confidence: 99%

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

Dana

Pathak

2020

Molecules

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“…52,53,67À71 In the zymogen and in the structure of a cathepsin L inhibitor complex, the S2 subsite is occupied by a phenylalanine residue. 72,73 In P3, major specificity determinants are absent, and the occurrence of individual amino acids does not exceed their natural abundance by more than 2-fold. Within P6 ÀP6 0 , the highest occurrence of methionine is found in P3, while the occurrences of phenylalanine, isoleucine, and leucine are only surpassed by their predominant presence in P2.…”

Section: Cathepsin L Specificitymentioning

confidence: 99%

Proteomic Identification of Protease Cleavage Sites Characterizes Prime and Non-prime Specificity of Cysteine Cathepsins B, L, and S

et al. 2011

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Cysteine cathepsins mediate proteome homeostasis and have pivotal functions in diseases such as cancer. To better understand substrate recognition by cathepsins B, L, and S, we applied proteomic identification of protease cleavage sites (PICS) for simultaneous profiling of prime and non-prime specificity. PICS profiling of cathepsin B endopeptidase specificity highlights strong selectivity for glycine in P3' due to an occluding loop blocking access to the primed subsites. In P1', cathepsin B has a partial preference for phenylalanine, which is not found for cathepsins L and S. Occurrence of P1' phenylalanine often coincides with aromatic residues in P2. For cathepsin L, PICS identifies 845 cleavage sites, representing the most comprehensive PICS profile to date. Cathepsin L specificity is dominated by the canonical preference for aromatic residues in P2 with limited contribution of prime-site selectivity determinants. Profiling of cathepsins B and L with a shorter incubation time (4 h instead of 16 h) did not reveal time-dependency of individual specificity determinants. Cathepsin S specificity was profiled at pH 6.0 and 7.5. The PICS profiles at both pH values display a high degree of similarity. Cathepsin S specificity is primarily guided by aliphatic residues in P2 with limited importance of prime-site residues.

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“…In order to test for the selectivity toward T. vaginalis protein targets over human isozymes, molecular docking of the phytochemical ligands was also carried out on human PNP (HsPNP, PDB 3BGS [33] and 3INY [34]); human TPI (HsTPI, PDB 2JK2 [35] and 4POC [36]); human cathepsin K (HsCatK, PDB 1MEM [37] and 1U9V [38]); and human cathepsin L (HsCatL, PDB 3HWN [39] and 3OF8 [40]). …”

Section: Methodsmentioning

confidence: 99%

Natural Products as New Treatment Options for Trichomoniasis: A Molecular Docking Investigation

et al. 2017

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Trichomoniasis, caused by the parasitic protozoan Trichomonas vaginalis, is the most common non-viral sexually-transmitted disease, and there can be severe complications from trichomoniasis. Antibiotic resistance in T. vaginalis is increasing, but there are currently no alternatives treatment options. There is a need to discover and develop new chemotherapeutic alternatives. Plant-derived natural products have long served as sources for new medicinal agents, as well as new leads for drug discovery and development. In this work, we have carried out an in silico screening of 952 antiprotozoal phytochemicals with specific protein drug targets of T. vaginalis. A total of 42 compounds showed remarkable docking properties to T. vaginalis methionine gamma-lyase (TvMGL) and to T. vaginalis purine nucleoside phosphorylase (TvPNP). The most promising ligands were polyphenolic compounds, and several of these showed docking properties superior to either co-crystallized ligands or synthetic enzyme inhibitors.

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Structural basis for reversible and irreversible inhibition of human cathepsin L by their respective dipeptidyl glyoxal and diazomethylketone inhibitors

Cited by 30 publications

References 33 publications

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

Proteomic Identification of Protease Cleavage Sites Characterizes Prime and Non-prime Specificity of Cysteine Cathepsins B, L, and S

Natural Products as New Treatment Options for Trichomoniasis: A Molecular Docking Investigation

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