Structural studies of cysteine proteases and their inhibitors.

Grzonka, Zbigniew; Jankowska, Elżbieta; Kasprzykowski, Franciszek; Kasprzykowska, Regina; Łankiewicz, Leszek; Wiczk, Wiesław; Wieczerzak, Ewa; Ciarkowski, Jerzy; Drabik, Piotr; Janowski, Robert; Kozak, Maciej; Jaskólski, M.; Grubb, Anders

doi:10.18388/abp.2001_5108

Cited by 119 publications

(96 citation statements)

References 95 publications

(87 reference statements)

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“…The best characterized family of cysteine proteases is the 'papain' that includes mammalian lysosomal cathepsin where the 'papain-fold' catalytic dyad (Cys25-His159) is evolutionarily preserved in all known eukaryotic papain-like cysteine protaseses (Grzonka et al, 2001). In HCoV-229E PL1pro, the conserved catalytic 'Cys1054-His1205' dyad was found to be indispensable for its proteolytic activity (Herold et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Proteases are classified according to their catalytic site into four major classes: cysteine (thiol) proteases, serine proteases, aspartyl (acid) proteases, and metalloproteases. Of the 21 families of cysteine proteses discovered so far, almost half of them are coded by viruses (Grzonka et al, 2001). The best characterized family of cysteine proteases is the 'papain' family characterized by a two-domain structure that contains an active site (catalytic pocket) for substrate binding.…”

Section: Introductionmentioning

confidence: 99%

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Molecular modeling and analysis of hepatitis E virus (HEV) papain-like cysteine protease

Parvez

Khan

2014

Virus Research

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The biochemical or biophysical characterization of a papain-like cysteine protease in HEV ORF1-encoded polyprotein still remains elusive. Very recently, we have demonstrated the indispensability of ORF1 protease-domain cysteines and histidines in HEV replication, ex vivo (Parvez, 2013). In this report, the polyprotein partial sequences of HEV strains and genetically-related RNA viruses were analyzed, in silico. Employing the consensus-prediction results of RUBV-p(150) protease as structural-template, a 3D model of HEV-protease was deduced. Similar to RUBV-p(150), a 'papain-like β-barrel fold' structurally confirmed the classification of HEV-protease. Further, we recognized a catalytic 'Cys434-His443' dyad homologue of RUBV-p(150) (Cys1152-His1273) and FMDV-L(pro) (Cys51-His148) in line with our previous mutational analysis that showed essentiality of 'His443' but not 'His590' in HEV viability. Moreover, a RUBV 'Zn(2+) binding motif' (Cys1167-Cys1175-Cys1178-Cys1225-Cys1227) equivalent of HEV was identified as 'Cys457-His458-Cys459 and Cys481-Cys483' residues within the 'β-barrel fold'. Notably, unlike RUBV, 'His458' also clustered therein, that was in conformity with the consensus cysteine protease 'Zn(2+)-binding motif'. By homology, we also proposed an overlapping 'Ca(2+)-binding site' 'D-X-[DNS]-[ILVFYW]-[DEN]-G-[GP]-XX-DE' signature, and a 'proline-rich motif' interacting 'tryptophan (W437-W472)' module in the modeled structure. Our analysis of the predicted model therefore, warrants critical roles of the 'catalytic dyad' and 'divalent metal-binding motifs' in HEV protease structural-integrity, ORF1 self-processing, and RNA replication. This however, needs further experimental validations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular modeling and analysis of hepatitis E virus (HEV) papain-like cysteine protease

Parvez

Khan

2014

Virus Research

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“…Cystatin C is the inhibitor of cysteine proteases [27]. It could be regulated by ubiquitin through IRF8 in the networks.…”

Section: D-dige and Uplc-q/tof Ms Showed Decrease In The Ms Groupmentioning

confidence: 99%

Quantitative proteomic analysis of the cerebrospinal fluid of patients with multiple sclerosis

ShiLian

Bai

Qin

et al. 2009

J Cellular Molecular Medi

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The diagnosis of multiple sclerosis (MS) is challenging for the lack of a specific diagnostic test. Recent researches in quantitative proteomics, however, offer new opportunities for biomarker discovery and the study of disease pathogenesis. To find more potential protein biomarkers, we used two technologies, 2-dimensional fluorescence difference in-gel electrophoresis (2D-DIGE), followed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and ultra-performance liquid chromato-graph coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS), to quantitatively analyse differential proteomic expression in the cerebrospinal fluid (CSF) between patients with MS (the experiment group) and patients with other neurological diseases (ONDs; the control group). Analysis by the former technology identified more than 43 different protein spots (39 proteins), of which 17 spots (13 proteins) showed more than 1.5-fold difference in abundance as analysed by DeCyder software (GE Healthcare, Piscataway. NJ, USA) between the MS and the ONDs groups. The expression of five protein spots was elevated and the expression of 12 protein spots was decreased in the MS group. Meanwhile, the latter method, UPLC/Q-TOF MS showed 68 different proteins. There were 45 proteins with a difference of more than 1.5 folds between the two groups, in which the expression of 20 proteins was elevated and the expression of 25 proteins was decreased in the MS group. Data provided by the two methods indicated that the proteins overlapped ratio was 27% in the 26 significant proteins that had the same regulation tendency. The differential CSF proteins were analysed further by biological network and it revealed interaction of them. The subsequent ELISA measuring the concentration of cystatin C (P < 0.01), which was one of the proteins discovered simultaneously with the two technologies, confirmed the results of the two quantitative proteomic analysis. The combination of the two quantitative proteomic technologies was helpful in discovering differentially expressed proteins that may have a connection with MS disease physiology and serve as useful biomarkers for diagnosis and treatment of MS diseases.

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“…8 In addition, this conserved cysteine was of interest given that it was not observed in a conserved motif commonly associated with either formation of disulfide bonds used in structure stabilization, 9 iron-sulfur clusters, 10 redox control, 11 or nucleophilic activity, such as in cysteine proteases. 12 Taken together, this information indicated that the conserved cysteine found at position 127 (M. jannaschii numbering) may have an important role in either the enzymatic activity or structure of Ade's and thus the role of this cysteine was investigated. A combination of experimental and computational approaches was used to provide insight into the potential role of the conserved cysteine at position 127 in M. jannaschii.…”

Section: Introductionmentioning

confidence: 97%

Purine salvage in Methanocaldococcus jannaschii: Elucidating the role of a conserved cysteine in adenine deaminase

Miller

Bevan

et al. 2016

Proteins

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Adenine deaminases (Ade) and hypoxanthine/guanine phosphoribosyltransferases (Hpt) are widely distributed enzymes involved in purine salvage. Characterization of the previously uncharacterized Ade (MJ1459 gene product) and Hpt (MJ1655 gene product) are discussed here and provide insight into purine salvage in Methanocaldococcus jannaschii. Ade was demonstrated to use either Fe(II) and/or Mn(II) as the catalytic metal. Hpt demonstrated no detectable activity with adenine, but was equally specific for hypoxanthine and guanine with a kcat /KM of 3.2 × 10(7) and 3.0 × 10(7) s(- 1) M(- 1) , respectively. These results demonstrate that hypoxanthine and IMP are the central metabolites in purine salvage in M. jannaschii for AMP and GMP production. A conserved cysteine (C127, M. jannaschii numbering) was examined due to its high conservation in bacterial and archaeal homologues. To assess the role of this highly conserved cysteine in M. jannaschii Ade, site-directed mutagenesis was performed. It was determined that mutation to serine (C127S) completely abolished Ade activity and mutation to alanine (C127A) exhibited 10-fold decrease in kcat over the wild type Ade. To further investigate the role of C127, detailed molecular docking and dynamics studies were performed and revealed adenine was unable to properly orient in the active site in the C127A and C127S Ade model structures due to distinct differences in active site conformation and rotation of D261. Together this work illuminates purine salvage in M. jannaschii and the critical role of a cysteine residue in maintaining active site conformation of Ade. Proteins 2016; 84:828-840. © 2016 Wiley Periodicals, Inc.

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Structural studies of cysteine proteases and their inhibitors.

Cited by 119 publications

References 95 publications

Molecular modeling and analysis of hepatitis E virus (HEV) papain-like cysteine protease

Molecular modeling and analysis of hepatitis E virus (HEV) papain-like cysteine protease

Quantitative proteomic analysis of the cerebrospinal fluid of patients with multiple sclerosis

Purine salvage in Methanocaldococcus jannaschii: Elucidating the role of a conserved cysteine in adenine deaminase

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