Exploring Solanum tuberosum Epoxide Hydrolase Internal Architecture by Water Molecules Tracking

Mitusińska, Karolina; Magdziarz, Tomasz; Bzówka, Maria; Stańczak, Agnieszka; Góra, Artur

doi:10.3390/biom8040143

Cited by 19 publications

(27 citation statements)

References 56 publications

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“…It also provides additional support to the drug design and investigation of protein interior [29,37,38]. As we have shown in previous research, tracking of water molecules in the binding cavity combined with the local distribution approach can identify catalytic water positions [39]. Indeed, despite differences in the size and dynamics of the binding cavities of SARS-CoV and SARS-CoV-2 Mpros, the main identified water was always found in a position next to the H41 residue ( Figure 2), and this location is assumed to indicate catalytic water of Mpro replacing the missing third catalytic site amino acid [28].…”

Section: Discussionmentioning

confidence: 82%

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Bzówka

Mitusińska

Raczyńska

et al. 2020

IJMS

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156

194

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The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with those for a highly similar severe acute respiratory syndrome (SARS) Mpro protein. In spite of a high level of sequence similarity, the active sites in both proteins showed major differences in both shape and size, indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, analysis of the binding site's conformational changes during the simulation time indicated its flexibility and plasticity, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the protein with respect to flexible loop mutations indicated that the virus' mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.

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Section: Discussionmentioning

confidence: 82%

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Bzówka

Mitusińska

Raczyńska

et al. 2020

IJMS

Self Cite

156

194

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“…This structural and functional characterization of PsEstA is expected to provide a molecular platform for the comprehensive understanding of family VIII esterases as well as β-lactamase, although the physiological role of PsEstA still needs to be explored. In addition, considering the fact that very few enzymes of this family have been biochemically characterized and immobilized for biotechnological applications, PsEstA could be a promising target for biotechnological applications [49][50][51]. Further studies on PsEstA including mutagenesis of the key residues, in-depth kinetic analysis, and evaluation of enzyme-substrate complex formation will be necessary for a thorough understanding of this enzyme at the molecular level.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of a Novel Family VIII Esterase with β-Lactamase Activity (PsEstA) from Paenibacillus sp.

et al. 2019

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Molecular information about family VIII esterases, which have similarities with class C β-lactamases and penicillin-binding proteins, remains largely unknown. In this study, a novel family VIII esterase with β-lactamase activity (PsEstA) from Paenibacillus sp. was characterized using several biochemical and biophysical methods. PsEstA was effective on a broad range of substrates including tertiary butyl acetate, glyceryl tributyrate, glucose pentaacetate, olive oil, and p-nitrophenyl esters. Additionally, PsEstA hydrolyzed nitrocefin, cefotaxime, and 7-aminocephalosporanic acid. Interestingly, two forms of immobilized PsEstA (CLEAs-PsEstA and mCLEAs-PsEstA) showed high recycling property and enhanced stability, but hybrid nanoflowers (hNFs) of PsEstA require improvement. This study provides a molecular understanding of substrate specificities, catalytic regulation, and immobilization of PsEstA, which can be efficiently used in biotechnological applications.

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“…This can be attributed to the strong salt bridge and stable interactions observed in the charged catalytic site state and also the presence of the long N-terminal helix. The local distribution density of water molecules enables the identification of essential residues capable of trapping water molecules and it can also be used for conserved water identification or regulation of ligand access (43). In O1U1C, a very low water distribution density is found.…”

Section: Water Access In the Ub-bound Conformation Of Otub1 And Otub2mentioning

confidence: 99%

Activation and selectivity of OTUB-1 and OTUB-2 deubiquitinylases

Sivakumar¹,

Kumar²,

Naumann³

et al. 2020

Journal of Biological Chemistry

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The ovarian tumor domain (OTU) deubiquitinylating cysteine proteases OTUB1 and OTUB2 (OTU ubiquitin aldehyde binding 1 and 2) are representative members of the OTU subfamily of deubiquitinylases. Deubiquitinylation critically regulates a multitude of important cellular processes, such as apoptosis, cell signaling, and growth. Moreover, elevated OTUB expression has been observed in various cancers, including glioma, endometrial cancer, ovarian cancer, and breast cancer. Here, using molecular dynamics simulation approaches, we found that both OTUB1 and OTUB2 display a catalytic triad characteristic of proteases but differ in their configuration and protonation states. The OTUB1 protein had a prearranged catalytic site, with strong electrostatic interactions between the active-site residues His265 and Asp267. In OTUB2, however, the arrangement of the catalytic triad was different. In the absence of ubiquitin, the neutral states of the catalytic-site residues in OTUB2 were more stable, resulting in larger distances between these residues. Only upon ubiquitin binding did the catalytic triad in OTUB2 rearrange and bring the active site into a catalytically feasible state. An analysis of water access channels revealed only a few diffusion trajectories for the catalytically active form of OTUB1, whereas in OTUB2 the catalytic site was solvent-accessible, and a larger number of water molecules reached and left the binding pocket. Interestingly, in OTUB2, the catalytic residues His224 and Asn226 formed a stable hydrogen bond. We propose that the observed differences in activation kinetics, protonation states, water channels, and active-site accessibility between OTUB1 and OTUB2 may be relevant for the selective design of OTU inhibitors.

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Exploring Solanum tuberosum Epoxide Hydrolase Internal Architecture by Water Molecules Tracking

Cited by 19 publications

References 56 publications

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

Molecular Characterization of a Novel Family VIII Esterase with β-Lactamase Activity (PsEstA) from Paenibacillus sp.

Activation and selectivity of OTUB-1 and OTUB-2 deubiquitinylases

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