Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function

Ingólfsson, Helgi I.; Thakur, Pratima; Herold, Karl F.; Hobart, E. Ashley; Ramsey, Nicole; Periole, Xavier; Jong, Djurre H. de; Zwama, Martijn; Yilmaz, Duygu; Hall, Katherine C.; Maretzky, Thorsten; Hemmings, Hugh C.; Blobel, Carl P.; Marrink, Siewert J.; Koçer, Armağan; Sack, Jon T.; Andersen, Olaf S.

doi:10.1021/cb500086e

Cited by 263 publications

(346 citation statements)

References 84 publications

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“…These, their analogues and similar natural products persist in being followed up as drug leads and used as 'positive' controls even though their promiscuous actions are welldocumented 8,9 .…”

Section: All Pain No Gainmentioning

confidence: 99%

Chemistry: Chemical con artists foil drug discovery

Baell

Walters

2014

Nature

958

880

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Section: All Pain No Gainmentioning

confidence: 99%

Chemistry: Chemical con artists foil drug discovery

Baell

Walters

2014

Nature

958

880

View full text Add to dashboard Cite

“…2B). Concentrations higher than 10 μM were not attempted because capsaicin and other lipophilic molecules at higher concentrations will nonspecifically alter the activity of ion channels through perturbation of the membrane (21). Sequence logo of the alignment between TRPV1 and TRPV2 channels.…”

Section: Trpv2_quad Is Activated By Resiniferatoxin But Antagonized Bymentioning

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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“…A number of studies have identified curcumin as a membrane-modulating agent, for example, it could alter lipid bilayer properties and influence structurally and functionally unrelated proteins, including a wide range of membrane proteins (Ingolfsson et al, 2007(Ingolfsson et al, , 2014, We have previously reported that cellular membrane lipid raft is crucial in mediating BoHV-1 entry into MDBK cells (Zhu et al, 2010). Here we demonstrated that curcumin affected BoHV-1 entry into MDBK cells.…”

Section: Discussionmentioning

confidence: 53%

Curcumin inhibits bovine herpesvirus type 1 entry into MDBK cells

Zhu¹,

Ding²,

Zhang³

et al. 2015

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Summary. -The generation of antiviral drugs from herbs and other natural resources with traditionally longconfirmed effects is an efficient approach. So far, no herb or components from herbs that could inhibit bovine herpesvirus type 1 (BoHV-1) replication have been described. In this study, the antiviral effect of curcumin, a natural phenolic constituent of the spice turmeric, on BoHV-1 replication was evaluated in cell culture. We demonstrated that curcumin impairs BoHV-1 viral particles and affects the virus post-binding entry process. Furthermore, curcumin upregulated the proportion of the plasma membrane adopting a lipid raft conformation in MDBK cells, which supported the previous reports that curcumin can modulate the lipid bilayer. Though the antiviral mechanism of curcumin on BoHV-1 needs further study, we identified for the first time a component from herb that could inhibit BoHV-1 replication, in vitro.Keywords: BoHV-1; curcumin; lipid raft; virus entry * Corresponding author. E-mail: yzgqzhu@yzu.edu.cn; phone: +86-514-87311374. Abbreviations: BoHV-1 = bovine herpesvirus type 1; CTB-FITC = fluorescent cholera toxin B subunit; DMSO = dimethyl sulfoxide; HSV = herpes simplex virus; MβCD = methyl-β-cyclodextrin; MDBK = Madin-Darby bovine kidney; MOI = multiplicity of infection; MTT = 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; p.i. = post infection; TCID 50 = tissue culture infection dose 50%

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Phytochemicals Perturb Membranes and Promiscuously Alter Protein Function

Cited by 263 publications

References 84 publications

Chemistry: Chemical con artists foil drug discovery

Chemistry: Chemical con artists foil drug discovery

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

Curcumin inhibits bovine herpesvirus type 1 entry into MDBK cells

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