The importance of 3D protein structure in proteolytic processing is well known. However, despite the plethora of existing methods for predicting proteolytic sites, only a few of them utilize the ...structural features of potential substrates as predictors. Moreover, to our knowledge, there is currently no method available for predicting the structural susceptibility of protein regions to proteolysis. We developed such a method using data from CutDB, a database that contains experimentally verified proteolytic events. For prediction, we utilized structural features that have been shown to influence proteolysis in earlier studies, such as solvent accessibility, secondary structure, and temperature factor. Additionally, we introduced new structural features, including length of protruded loops and flexibility of protein termini. To maximize the prediction quality of the method, we carefully curated the training set, selected an appropriate machine learning method, and sampled negative examples to determine the optimal positive-to-negative class size ratio. We demonstrated that combining our method with models of protease primary specificity can outperform existing bioinformatics methods for the prediction of proteolytic sites. We also discussed the possibility of utilizing this method for bioinformatics prediction of other post-translational modifications.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) primarily enters the cell by binding the virus's spike (S) glycoprotein to the angiotensin-converting enzyme 2 receptor on the cell ...surface, followed by proteolytic cleavage by host proteases. Studies have identified furin and transmembrane protease serine 2 proteases in priming and triggering cleavages of the S glycoprotein, converting it into a fusion-competent form and initiating membrane fusion, respectively. Alternatively, SARS-CoV-2 can enter the cell through the endocytic pathway, where activation is triggered by lysosomal cathepsin L. However, other proteases are also suspected to be involved in both entry routes. In this study, we conducted a genome-wide bioinformatics analysis to explore the capacity of human proteases in hydrolyzing peptide bonds of the S glycoprotein. Predictive models of sequence specificity for 169 human proteases were constructed and applied to the S glycoprotein together with the method for predicting structural susceptibility to proteolysis of protein regions. After validating our approach on extensively studied S2' and S1/S2 cleavage sites, we applied our method to each peptide bond of the S glycoprotein across all 169 proteases. Our results indicate that various members of the proprotein convertase subtilisin/kexin type, type II transmembrane family serine protease, and kallikrein families, as well as specific coagulation factors, are capable of cleaving S2' or S1/S2 sites. We have also identified a potential cleavage site of cathepsin L at the K790 position within the S2' loop. Structural analysis suggests that cleavage of this site induces conformational changes similar to the cleavage at the R815 (S2') position, leading to the exposure of the fusion peptide and subsequent fusion with the membrane. Other potential cleavage sites and the influence of mutations in common SARS-CoV-2 variants on proteolytic efficiency are discussed.IMPORTANCEThe entry of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) into the cell, activated by host proteases, is considerably more complex in coronaviruses than in most other viruses and is not fully understood. There is evidence that other proteases beyond the known furin and transmembrane protease serine 2 can activate the spike protein. Another example of uncertainty is the cleavage site for the alternative endocytic route of SARS-CoV-2 entrance, which is still unknown. Bioinformatics methods, modeling protease specificity and estimating the structural susceptibility of protein regions to proteolysis, can aid in studying this topic by predicting the involved proteases and their cleavage sites, thereby substantially reducing the amount of experimental work. Elucidating the mechanisms of spike protein activation is crucial for preventing possible future coronavirus pandemics and developing antiviral drugs.
Bioinformatics-based prediction of protease substrates can help to elucidate regulatory proteolytic pathways that control a broad range of biological processes such as apoptosis and blood ...coagulation. The majority of published predictive models are position weight matrices (PWM) reflecting specificity of proteases toward target sequence. These models are typically derived from experimental data on positions of hydrolyzed peptide bonds and show a reasonable predictive power. New emerging techniques that not only register the cleavage position but also measure catalytic efficiency of proteolysis are expected to improve the quality of predictions or at least substantially reduce the number of tested substrates required for confident predictions. The main goal of this study was to develop new prediction models based on such data and to estimate the performance of the constructed models. We used data on catalytic efficiency of proteolysis measured for eight major human matrix metalloproteinases to construct predictive models of protease specificity using a variety of regression analysis techniques. The obtained results suggest that efficiency-based (quantitative) models show a comparable performance with conventional PWM-based algorithms, while less training data are required. The derived list of candidate cleavage sites in human secreted proteins may serve as a starting point for experimental analysis.
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•Protease specificity models can be built from quantitative protease profiling data.•Regression methods is applicable for the building of such predictive models.•These models perform at least as well as traditional quantitative PWMs.•Significantly smaller number of peptide substrates are required for training data.
Phytoneering in clinical practice Tsukanov, Anton Iu; Matveev, Evgenii V.
Consilium medicum,
12/2021, Letnik:
23, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The discovery of antibiotics almost 100 years ago seemed to have forever solved the issue of treating infectious diseases for humanity. However, the avalanche-like growth in antibiotic resistance ...requires the search for alternative methods of treatment, one of which is treatment with herbal products created according to the phytoneering concept. It is a technology that combines the enormous potential of medicinal plants (phyto) with the knowledge and methodology of modern pharmaceutical research (engineering). The article presents 2 clinical cases of the use of the herbal product Canephron N for the prevention of cystitis and acute urolithiasis common disorders in the practice of a urologist.
The dynamic behavior of the catalytic CO oxidation reaction on the metal surfaces (Pt, Pd) of different structures (single crystals Pt(1
0
0), Pd(1
1
0); microcrystals (Pt, Pd tips); nanoparticles ...(Pd/support)) has been studied experimentally by FEM, HREELS, TPR, TDS, MB techniques and kinetic Monte Carlo modeling. The CO, O
2 adsorption and CO
+
O
2 reaction was studied by HREELS, TPR and TDS. Sharp tips of Pt and Pd, several hundreds angstroms in radius, were used to perform
in situ investigations of the dynamic surface processes by FEM. HREELS studies on the Pt(1
0
0) surface demonstrate that the self-oscillations and waves propagation are connected with periodic changes in the surface structure of nanoplane (1
0
0)–(hex)
↔
(1
×
1), varying the catalytic property of metal. The fundamentally different feedback mechanism generating the kinetic oscillations has been identified on the Pd surfaces: the reversible subsurface oxygen formation, which modifies the adsorption and catalytic properties of the surface. Based on experimental results, two models for the CO
+
O
2 reaction on Pt(1
0
0) and Pd(1
1
0) surfaces are proposed for stochastic Monte Carlo modeling. Carbon monoxide spillover was taken into account in the stochastic model of oscillatory CO oxidation reaction over model Pd supported nanoparticles. The presence of CO
ads spillover determines the character of concentration waves over the Pd nanoparticle surface—oxygen wave propagates from the central particle part to the particle/support perimeter;—carbon monoxide wave moves in the opposite direction. The comprehensive study of CO, O
2 adsorption and CO
+
O
2 reaction in a row: single crystals
→
tips
→
nanoparticles have shown an identical nature of active centres over these metal surfaces.
Prostate cancer Kaprin, Andrei D.; Alekseev, Boris Ia; Matveev, Vsevolod B. ...
Sovremennaia onkologiia : zhurnal kafedry onkologii RMAPO dlia nepreryvnogo poslediplomnogo obrazovaniia,
08/2021, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Prostate cancer (RPP) is a malignant neoplasm that arises from the epithelium of the prostate gland gland (PJ). рак предстательной железы; клинические рекомендацииThethiology and pathogenesis of this ...disease remain poorly studied. Many studies are aimed at studying diet, food, hormonal impact, as well as infections in the etiology of the RLPG. The prevalence of RPL depends on ethnic and geographical features. The highest incidence of African Americans living in the United States (60% higher than that of white Americans), the least high - in the Chinese living in China 1. In addition to racial features, the risk factors of the RPG are considering the genetic predisposition, the age of men and nutritional features. The probability of developing a PJ tumor in a man who has one of the closest relatives of the first degree of kinship (father or brother) sick of the RLPG, is 1.8 times higher than in the population. If two relatives were sick or more (father and brother or both brothers), the risk of RPG increases in 5.51 and 7.71 times, respectively 2, 3. African Americans have an increased risk of identifying RPG, as well as a greater probability of detecting aggressive RPG 4. Also, the risk of RLPG is rising in men who use a large amount of animal fats 5.
Prostate cancer Andrei D. Kaprin; Boris Ia. Alekseev; Vsevolod B. Matveev ...
Sovremennaia onkologiia : zhurnal kafedry onkologii RMAPO dlia nepreryvnogo poslediplomnogo obrazovaniia,
08/2021, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Prostate cancer (RPP) is a malignant neoplasm that arises from the epithelium of the prostate gland gland (PJ). Thethiology and pathogenesis of this disease remain poorly studied. Many studies are ...aimed at studying diet, food, hormonal impact, as well as infections in the etiology of the RLPG. The prevalence of RPL depends on ethnic and geographical features. The highest incidence of African Americans living in the United States (60% higher than that of white Americans), the least high - in the Chinese living in China 1. In addition to racial features, the risk factors of the RPG are considering the genetic predisposition, the age of men and nutritional features. The probability of developing a PJ tumor in a man who has one of the closest relatives of the first degree of kinship (father or brother) sick of the RLPG, is 1.8 times higher than in the population. If two relatives were sick or more (father and brother or both brothers), the risk of RPG increases in 5.51 and 7.71 times, respectively 2, 3. African Americans have an increased risk of identifying RPG, as well as a greater probability of detecting aggressive RPG 4. Also, the risk of RLPG is rising in men who use a large amount of animal fats 5.
The dynamic behavior of the catalytic CO oxidation reaction on the metal surfaces (Pt, Pd) of different structures (single crystals Pt(1 0 0), Pd(1 1 0); microcrystals (Pt, Pd tips); nanoparticles ...(Pd/support)) has been studied experimentally by FEM, HREELS, TPR, TDS, MB techniques and kinetic Monte Carlo modeling. The CO, O sub(2) adsorption and CO + O sub(2) reaction was studied by HREELS, TPR and TDS. Sharp tips of Pt and Pd, several hundreds angstroms in radius, were used to perform in situ investigations of the dynamic surface processes by FEM. HREELS studies on the Pt(1 0 0) surface demonstrate that the self-oscillations and waves propagation are connected with periodic changes in the surface structure of nanoplane (1 0 0)-(hex) <--> (1 x 1), varying the catalytic property of metal. The fundamentally different feedback mechanism generating the kinetic oscillations has been identified on the Pd surfaces: the reversible subsurface oxygen formation, which modifies the adsorption and catalytic properties of the surface. Based on experimental results, two models for the CO + O sub(2) reaction on Pt(1 0 0) and Pd(1 1 0) surfaces are proposed for stochastic Monte Carlo modeling. Carbon monoxide spillover was taken into account in the stochastic model of oscillatory CO oxidation reaction over model Pd supported nanoparticles. The presence of CO sub(ads) spillover determines the character of concentration waves over the Pd nanoparticle surface - oxygen wave propagates from the central particle part to the particle/support perimeter; - carbon monoxide wave moves in the opposite direction. The comprehensive study of CO, O sub(2) adsorption and CO + O sub(2) reaction in a row: single crystals --> tips --> nanoparticles have shown an identical nature of active centres over these metal surfaces.
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