CAVER Analyst 1.0: graphic tool for interactive visualization and analysis of tunnels and channels in protein structures

Kozlíková, Barbora; Šebestová, Eva; Šustr, Vilém; Brezovský, Jan; Strnad, Ondřej; Daniel, Lukáš; Bednář, David; Pavelka, Antonín; Maňák, Martin; Bezděka, Martin; Beneš, Petr; Kotry, Matúš; Góra, Artur; Damborský, Jiřı́; Sochor, Jiří­

doi:10.1093/bioinformatics/btu364

Cited by 129 publications

(111 citation statements)

References 12 publications

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“…The volume of the binding pockets on TRPV1 and TRPV2 was measured by CAVER Analyst, version 1.0 (63). University of California, San Francisco (UCSF) Chimera (64) software, version 1.9, was used to render all graphs of docking models.…”

Section: Methodsmentioning

confidence: 99%

Rational design and validation of a vanilloid-sensitive TRPV2 ion channel

Yang

Yarov‐Yarovoy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Vanilloids activation of TRPV1 represents an excellent model system of ligand-gated ion channels. Recent studies using cryo-electron microcopy (cryo-EM), computational analysis, and functional quantification revealed the location of capsaicin-binding site and critical residues mediating ligand-binding and channel activation. Based on these new findings, here we have successfully introduced high-affinity binding of capsaicin and resiniferatoxin to the vanilloid-insensitive TRPV2 channel, using a rationally designed minimal set of four point mutations (F467S-S498F-L505T-Q525E, termed TRPV2_Quad). We found that binding of resiniferatoxin activates TRPV2_Quad but the ligand-induced open state is relatively unstable, whereas binding of capsaicin to TRPV2_Quad antagonizes resiniferatoxin-induced activation likely through competition for the same binding sites. Using Rosettabased molecular docking, we observed a common structural mechanism underlying vanilloids activation of TRPV1 and TRPV2_Quad, where the ligand serves as molecular "glue" that bridges the S4-S5 linker to the S1-S4 domain to open these channels. Our analysis revealed that capsaicin failed to activate TRPV2_Quad likely due to structural constraints preventing such bridge formation. These results not only validate our current working model for capsaicin activation of TRPV1 but also should help guide the design of drug candidate compounds for this important pain sensor.on channels constitute the second largest family of drug targets for therapeutics (1-3); therefore, understanding their gating mechanisms by small-molecule ligands is critical for both basic and translational research. Capsaicin activation of the pain-sensing transient receptor potential vanilloid 1 (TRPV1) ion channel represents an outstanding model system for understanding liganddependent gating process (4), because capsaicin not only potently activates the channel with a submicromolar EC 50 (5) but also effectively stabilizes the channel at high open probability (6-8). Moreover, capsaicin activation is highly selective for TRPV1 channel (5). Previous mutagenesis (9, 10) and cryo-EM studies (11,12) have shown that capsaicin binds near the third (S3) and fourth (S4) transmembrane segments of TRPV1 (Fig. 1A). Based on the high-resolution cryo-EM structures, we have used a combination of computational and functional assays to reveal that capsaicin takes a "tail-up, head-down" configuration in the ligand-binding pocket (6) (Fig. 1B). The aliphatic tail forms extensive but nonspecific van der Waals (VDW) interactions with residues lining the binding pocket, whereas the vanillyl group (head) and the amide group (neck) of capsaicin form a hydrogen bond with E571 on S4-S5 linker and T551 on S4, respectively. To activate TRPV1, VDW interactions first secure capsaicin in the pocket and the neck of capsaicin forms a hydrogen bond with T551. This is followed by the formation of another hydrogen bond between the head and E571, which stabilizes the outward conformation of S4-S5 linker to open the chann...

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Section: Methodsmentioning

confidence: 99%

Rational design and validation of a vanilloid-sensitive TRPV2 ion channel

Yang

Yarov‐Yarovoy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The models were comprehensively analyzed using PyMol 1.1 (http://pymol.org/) to check for the presence of a lid, and the existence and orientation of the catalytic triad. Putative intramolecular tunnels were modeled using Caver analyst 1.0 [39] taking the catalytic serine in each candidate as starting point.…”

Section: Methodsmentioning

confidence: 99%

Evolutionary history of versatile-lipases from Agaricales through reconstruction of ancestral structures

Barriuso

Martı́nez

2017

BMC Genomics

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BackgroundFungal “Versatile carboxylic ester hydrolases” are enzymes with great biotechnological interest. Here we carried out a bioinformatic screening to find these proteins in genomes from Agaricales, by means of searching for conserved motifs, sequence and phylogenetic analysis, and three-dimensional modeling. Moreover, we reconstructed the molecular evolution of these enzymes along the time by inferring and analyzing the sequence of ancestral intermediate forms.ResultsThe properties of the ancestral candidates are discussed on the basis of their three-dimensional structural models, the hydrophobicity of the lid, and the substrate binding intramolecular tunnel, revealing all of them featured properties of these enzymes. The evolutionary history of the putative lipases revealed an increase on the length and hydrophobicity of the lid region, as well as in the size of the substrate binding pocket, during evolution time. These facts suggest the enzymes’ specialization towards certain substrates and their subsequent loss of promiscuity.ConclusionsThese results bring to light the presence of different pools of lipases in fungi with different habitats and life styles. Despite the consistency of the data gathered from reconstruction of ancestral sequences, the heterologous expression of some of these candidates would be essential to corroborate enzymes’ activities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3419-2) contains supplementary material, which is available to authorized users.

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“…CAVER Analyst 1.0 was employed to evaluate accessibility of clefts and cavities for transporting the modulators into MTPa. The program identifies and visualizes routes from the interior of the protein structure to the bulk solvent [45]. CAVER Analyst was used for the analysis of MD snapshots at every 500 ps from a 10ns classical MD simulation of MT.…”

Section: Tunnel Analysismentioning

confidence: 99%

Non-specific binding sites help to explain mixed inhibition in mushroom tyrosinase activities

Hassani

Haghbeen

Fazli

2016

European Journal of Medicinal Chemistry

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CAVER Analyst 1.0: graphic tool for interactive visualization and analysis of tunnels and channels in protein structures

Abstract: CAVER Analyst is a multi-platform software written in JAVA. Binaries and documentation are freely available for non-commercial use at http://www.caver.cz.

Cited by 129 publications

References 12 publications

Rational design and validation of a vanilloid-sensitive TRPV2 ion channel

Rational design and validation of a vanilloid-sensitive TRPV2 ion channel

Evolutionary history of versatile-lipases from Agaricales through reconstruction of ancestral structures

Non-specific binding sites help to explain mixed inhibition in mushroom tyrosinase activities

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