C1 Domains: Structure and Ligand-Binding Properties

Das, Joydip; Rahman, Ghazi Muhammad Sayedur

doi:10.1021/cr300481j

Cited by 90 publications

(136 citation statements)

References 235 publications

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“…19 PKCs belong to the superfamily of serine threonine kinases that play a central role in intracellular signal transduction implicated in a wide variety of cellular functions. 19 It had been shown that an oxygenated functionality at C-20 and the O-acyl function at C-13 of tigliane-type diterpenes are essential for their interaction with PKC, as well as their skin-irritant and tumor-promoting bioactivities. 16 Nonetheless, the hydrophobicity of phorbol esters appears to be a critical factor that contributes to these biological properties, because it induces different translocation patterns of PKCs in the cell.…”

Section: Journal Of Natural Productsmentioning

confidence: 99%

“…17,18 In particular, phorbol esters activate conventional and novel PKCs by interacting with their cysteinerich C1 domain, triggering a series of interlinking signaling pathways. 19 The clinical launch of Picato (ingenol-3-mebutate, PEP005), a broad PKC modulator isolated from E. peplus for the treatment of a precancerous skin condition (actinic keratosis), 20 along with recent results on EBC-46 (tiglianetype), which shows promise in curing various tumors by a single intralesional injection in a preclinical model for cancer, 21 highlight the therapeutic potential of diterpene esters endowed with PKC modulation abilities.In the present investigation, the antiviral potential of 29 diterpene esters (1−29), belonging to tigliane (1−25), ingenane (26−28), and daphnane (29) types, was evaluated in cell culture against CHIKV, HIV-1, and HIV-2. The aim of this study was to enhance knowledge of the structure−activity relationships (SARs) for these chemical classes and to investigate a possible correlation between their anti-CHIKV and anti-HIV activities.…”

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Antiviral Activity of Diterpene Esters on Chikungunya Virus and HIV Replication

et al. 2015

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Recently, new daphnane, tigliane, and jatrophane diterpenoids have been isolated from various Euphorbiaceae species, of which some have been shown to be potent inhibitors of chikungunya virus (CHIKV) replication. To further explore this type of compound, the antiviral activity of a series of 29 commercially available natural diterpenoids was evaluated. Phorbol-12,13-didecanoate (11) proved to be the most potent inhibitor, with an EC50 value of 6.0 ± 0.9 nM and a selectivity index (SI) of 686, which is in line with the previously reported anti-CHIKV potency for the structurally related 12-O-tetradecanoylphorbol-13-acetate (13). Most of the other compounds exhibited low to moderate activity, including an ingenane-type diterpene ester, compound 28, with an EC50 value of 1.2 ± 0.1 μM and SI = 6.4. Diterpene compounds are known also to inhibit HIV replication, so the antiviral activities of compounds 1-29 were evaluated also against HIV-1 and HIV-2. Tigliane- (4β-hydroxyphorbol analogues 10, 11, 13, 15, 16, and 18) and ingenane-type (27 and 28) diterpene esters were shown to inhibit HIV replication in vitro at the nanomolar level. A Pearson analysis performed with the anti-CHIKV and anti-HIV data sets demonstrated a linear relationship, which supported the hypothesis made that PKC may be an important target in CHIKV replication.

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Section: Journal Of Natural Productsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Antiviral Activity of Diterpene Esters on Chikungunya Virus and HIV Replication

et al. 2015

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“…The functional studies of course were determined on the tertiary complex of C1 domainligand-lipid bilayer. The C1 domains with high phorbol ester binding affinity all have larger, hydrophobic residues at the 8 position (1,18,64) that interact with Leu 21 and help stabilize the binding loops. This effect may not be captured in the simulations with the binary complex, which lacks the effect of the lipid environment on the ligand positioning and the binding loops.…”

Section: The Quadruply Mutated Rasgrp2 Caused Enhanced Rap1mentioning

confidence: 99%

Structural Basis for the Failure of the C1 Domain of Ras Guanine Nucleotide Releasing Protein 2 (RasGRP2) to Bind Phorbol Ester with High Affinity

Czikora

Lundberg

Abramovitz

et al. 2016

Journal of Biological Chemistry

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The C1 domain represents the recognition module for diacylglycerol and phorbol esters in protein kinase C, Ras guanine nucleotide releasing protein (RasGRP), and related proteins. 3 H]phorbol 12,13-dibutyrate binding was determined; it decreased in going from the single S8Y mutant to the quadruple mutant. The full-length RasGRP2 protein with the mutated C1 domains also showed strong phorbol ester binding, albeit modestly weaker than that of the C1 domain alone (K d ‫؍‬ 8.2 ؎ 1.1 nM for the full-length protein containing all four mutations), and displayed translocation in response to phorbol ester. RasGRP2 is a guanyl exchange factor for Rap1. Consistent with the ability of phorbol ester to induce translocation of the full-length Ras-GRP2 with the mutated C1 domain, phorbol ester enhanced the ability of the mutated RasGRP2 to activate Rap1. Modeling confirmed that the four mutations helped the binding cleft maintain a stable conformation. RasGRP2 is exceptional in that its

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“…In particular tigliane-type esters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA) (13), phorbol-12,13-didecanoate (11) and prostratin (21), were found to be potent and selective inhibitors of CHIKV (and HIV) replication in vitro [10,11]. TPA, along with other phorbol esters, are known to possess pro-inflammatory and tumor-promoting activities [12][13][14][15] through broad activation of PKCs (Protein kinase C isoenzymes), which makes them unsuitable as antiviral drugs for clinical use [16,17].…”

Section: Introductionmentioning

confidence: 99%

LC-MS2-Based dereplication of Euphorbia extracts with anti-Chikungunya virus activity

et al. 2015

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Recently, phorbol esters from Euphorbiaceae have been shown to elicit potent and selective antiviral activity on the replication of Chikungunya virus (CHIKV) in cell culture. With the objective to found new compounds with anti-CHIKV activities, 45 extracts from various plant parts of 11 Mediterranean Euphorbia and one Mercurialis species were evaluated for selective inhibition of CHIKV replication. All EtOAc extracts, especially those prepared from latex, exhibited significant and selective antiviral activity in a Chikungunya virus-cell-based assay. An LC-MS(2) dereplication method was then developed to investigate whether known diterpenoids with anti-CHIKV activity, such as the potent anti-CHIKV 12-O-tetradecanoylphorbol-13-acetate (TPA), phorbol-12,13-didecanoate, and prostratin as well as 24 other commercially available diterpenoids of tigliane-, ingenane-, and daphnane-type for which the anti-CHIKV activity have been established in advance (Nothias-Scaglia et al. 2015), were present in the Euphorbia extracts. Only ingenol-3-mebutate, 13-O-isobutyryl-12-deoxyphorbol-20-acetate, and ingenol-3,20-dibenzoate, all exhibiting weak anti-CHIKV activities, were detected in the EtOAc extracts of Euphorbia peplus, Euphorbia segetalis ssp. pinea, and Euphorbia pithyusa ssp. pithyusa. Given the potent anti-CHIKV activities of these Euphorbia extracts, the present study suggested that their antiviral activities are probably due to untargeted diterpenoids.

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C1 Domains: Structure and Ligand-Binding Properties

Cited by 90 publications

References 235 publications

Antiviral Activity of Diterpene Esters on Chikungunya Virus and HIV Replication

Antiviral Activity of Diterpene Esters on Chikungunya Virus and HIV Replication

Structural Basis for the Failure of the C1 Domain of Ras Guanine Nucleotide Releasing Protein 2 (RasGRP2) to Bind Phorbol Ester with High Affinity

LC-MS2-Based dereplication of Euphorbia extracts with anti-Chikungunya virus activity

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