Caver Web 1.0: identification of tunnels and channels in proteins and analysis of ligand transport

Štourač, Jan; Vávra, Ondřej; Kokkonen, Piia; Filipovič, Jiří; Pinto, Gaspar; Brezovský, Jan; Damborský, Jiřı́; Bednář, David

doi:10.1093/nar/gkz378

Cited by 198 publications

(175 citation statements)

References 54 publications

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“…The main wider tunnel has an average tunnel length of 8.8 Å, its average bottleneck radius is 2.2 Å, and its average tunnel throughput is 0.90 (this parameter describes the probability that the pathway is used as a route for transport of the substances, maximal value is 1.0). The second tunnel has an average length of 15.2 Å, an average bottleneck radius of 1.4 Å, and an average tunnel throughput of 0.67 [34]. The output of CAVER 3.0 provided us with the necessary data for CAVERDOCK computational analysis of the time evolution of individual pathways.…”

Section: Anrut Structure and Description Of Substrate Tunnelsmentioning

confidence: 99%

Dual Substrate Specificity of the Rutinosidase from Aspergillus niger and the Role of Its Substrate Tunnel

Brodsky

Kutý

Cvačka

et al. 2020

IJMS

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Rutinosidases (α-l-rhamnopyranosyl-(1-6)-β-d-glucopyranosidases, EC 3.2.1.168, CAZy GH5) are diglycosidases that cleave the glycosidic bond between the disaccharide rutinose and the respective aglycone. Similar to many retaining glycosidases, rutinosidases can also transfer the rutinosyl moiety onto acceptors with a free –OH group (so-called transglycosylation). The recombinant rutinosidase from Aspergillus niger (AnRut) is selectively produced in Pichia pastoris. It can catalyze transglycosylation reactions as an unpurified preparation directly from cultivation. This enzyme exhibits catalytic activity towards two substrates; in addition to rutinosidase activity, it also exhibits β-d-glucopyranosidase activity. As a result, new compounds are formed by β-glucosylation or rutinosylation of acceptors such as alcohols or strong inorganic nucleophiles (NaN3). Transglycosylation products with aliphatic aglycones are resistant towards cleavage by rutinosidase, therefore, their side hydrolysis does not occur, allowing higher transglycosylation yields. Fourteen compounds were synthesized by glucosylation or rutinosylation of selected acceptors. The products were isolated and structurally characterized. Interactions between the transglycosylation products and the recombinant AnRut were analyzed by molecular modeling. We revealed the role of a substrate tunnel in the structure of AnRut, which explained the unusual catalytic properties of this glycosidase and its specific transglycosylation potential. AnRut is attractive for biosynthetic applications, especially for the use of inexpensive substrates (rutin and isoquercitrin).

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Section: Anrut Structure and Description Of Substrate Tunnelsmentioning

confidence: 99%

Dual Substrate Specificity of the Rutinosidase from Aspergillus niger and the Role of Its Substrate Tunnel

Brodsky

Kutý

Cvačka

et al. 2020

IJMS

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“…For probing the structure and function of sugar transporters on targeted carbon molecules, identification of tunnels is the next key step. In order to predict the theoretical position of xylose when binding with CCM_06358, Caver Web 1.0 [52] was used to predict a catalytic pocket located at the TM1 and TM2 (residues 38 to 69) with high druggability of 0.89 ( Figure 5B). The xylose at this opening position was docked, and the binding pose showed that the xylose interacted with Gln50, Met311, and Thr315 through H-bonds ( Figure S2A).…”

Section: Annotated Molecular Structure and Transport Pathway Of A Selmentioning

confidence: 99%

Probing Carbon Utilization of Cordyceps militaris by Sugar Transportome and Protein Structural Analysis

Sirithep

Xiao

Raethong

et al. 2020

Cells

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Beyond comparative genomics, we identified 85 sugar transporter genes in Cordyceps militaris, clustering into nine subfamilies as sequence-and phylogenetic-based functional classification, presuming the versatile capability of the fungal growths on a range of sugars. Further analysis of the global gene expression patterns of C. militaris showed 123 genes were significantly expressed across the sucrose, glucose, and xylose cultures. The sugar transporters specific for pentose were then identified by gene-set enrichment analysis. Of them, the putative pentose transporter, CCM_06358 gene, was highest expressed in the xylose culture, and its functional role in xylose transport was discovered by the analysis of conserved structural motifs. In addition, a battery of molecular modeling methods, including homology modeling, transport pathway analysis, residue interaction network combined with molecular mechanics Poisson-Boltzmann surface area simulation (MM-PBSA), was implemented for probing the structure and function of the selected pentose transporter (CCM_06358) as a representative of sugar transportome in C. militaris. Considering the network bottlenecks and structural organizations, we further identified key amino acids (Phe38 and Trp441) and their interactions with other residues, contributing the xylose transport function, as verified by binding free energy calculation. The strategy used herein generated remarkably valuable biological information, which is applicable for the study of sugar transportome and the structure engineering of targeted transporter proteins that might link to the production of bioactive compounds derived from xylose metabolism, such as cordycepin.

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“…Then, the AutoDock 4.2.6 software was employed to predict the binding mode between HSF-1 and Sch A [22]. The binding site was predicted by Caver Web server, and covered by a grid box size of 22.5 × 22.5 × 22.5Å dimensions [23]. The globe conformational sampling was set to trials of 200 dockings, and settings were set as default.…”

Section: Molecular Dynamics Simulation Of the Complex Between Hsf-1 Amentioning

confidence: 99%

Schizandrin A exhibits potent anticancer activity in colorectal cancer cells by inhibiting heat shock factor 1

Chen

Zheng

et al. 2020

Bioscience Reports

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Heat shock factor 1 (HSF1) is a powerful multifaceted oncogenic modifier that plays a role in maintaining the protein balance of cancer cells under various stresses. In recent studies, there have been reports of increased expression of HSF1 in colorectal cancer (CRC) cells, and the depletion of the HSF1 gene knockdown has inhibited colon cancer growth both in vivo and in vitro. Therefore, HSF1 is a promising target for colon cancer treatment and chemoprevention. In the present study, we found that Schizandrin A (Sch A) significantly inhibited the growth of CRC cell lines by inducing cell cycle arrest, apoptosis and death. Through HSE luciferase reporter assay and quantitative PCR (qPCR), we identified Sch A as a novel HSF1 inhibitor. In addition, Sch A could effectively inhibit the induction of HSF1 target proteins such as heat-shock protein (HSP) 70 (HSP70) and HSP27, whether in heat shock or normal temperature culture. In the Surface Plasmon Resonance (SPR) experiment, Sch A showed moderate affinity with HSF1, further confirming that Sch A might be a direct HSF1 inhibitor. The molecular docking and molecular dynamic simulation results of HSF1/Sch A suggested that Sch A formed key hydrogen bond and hydrophobic interactions with HSF1, which may contribute to its potent HSF1 inhibition. These findings provide clues for the design of novel HSF1 inhibitors and drug candidates for colon cancer treatment.

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Caver Web 1.0: identification of tunnels and channels in proteins and analysis of ligand transport

Cited by 198 publications

References 54 publications

Dual Substrate Specificity of the Rutinosidase from Aspergillus niger and the Role of Its Substrate Tunnel

Dual Substrate Specificity of the Rutinosidase from Aspergillus niger and the Role of Its Substrate Tunnel

Probing Carbon Utilization of Cordyceps militaris by Sugar Transportome and Protein Structural Analysis

Schizandrin A exhibits potent anticancer activity in colorectal cancer cells by inhibiting heat shock factor 1

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