YM-254890 analogues, novel cyclic depsipeptides with Gαq/11 inhibitory activity from Chromobacterium sp. QS3666

Taniguchi, Masatoshi; Suzumura, Ken-ichi; Nagai, Koji; Kawasaki, Tomihisa; Takasaki, Jun; Sekiguchi, Mitsuhiro; Moritani, Yumiko; Saito, Tetsu; Hayashi, Kazumi; Fujita, Shigeo; Tsukamoto, Shin‐ichi; Suzuki, Kenichi

doi:10.1016/j.bmc.2004.04.006

Cited by 41 publications

(77 citation statements)

References 8 publications

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“…2C) with seven amide bonds. YM-254890 in our complex may exhibit a combination of cisor trans-amide bond conformations identical to the major conformer suggested by a previous NMR analysis in solution (18) and display an overall conformation of a folded V-shape, which is in part stabilized by intramolecular hydrogen bonds (Fig. 2D and Fig.…”

Section: Resultssupporting

confidence: 72%

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

Nishimura

Kitano

Takasaki

et al. 2010

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

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Heterotrimeric GTP-binding proteins (G proteins) transmit extracellular stimuli perceived by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. Hundreds of GPCRs exist in humans and are the targets of a large percentage of the pharmaceutical drugs used today. Because G proteins are regulated by GPCRs, small molecules that directly modulate G proteins have the potential to become therapeutic agents. However, strategies to develop modulators have been hampered by a lack of structural knowledge of targeting sites for specific modulator binding. Here we present the mechanism of action of the cyclic depsipeptide YM-254890, which is a recently discovered G q -selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of α subunit of G q protein (Gα q ) by inhibiting the GDP release from Gα q . X-ray crystal structure analysis of the Gα q βγ–YM-254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the Gα q . The binding stabilizes an inactive GDP-bound form through direct interactions with switch I and impairs the linker flexibility. Our studies provide a novel targeting site for the development of small molecules that selectively inhibit each Gα subunit and an insight into the molecular mechanism of G protein activation.

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Section: Resultssupporting

confidence: 72%

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

Nishimura

Kitano

Takasaki

et al. 2010

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

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229

317

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“…Zn 2+ -dependent activation of this pathway was also shown in neurons (Besser et al 2009). Inhibitors of Gαq Taniguchi et al 2004), inositol 1,4,5-trisphosphate (IP3) receptor, and phospholipase C (PLC) attenuated this Zn 2+ -dependent Ca 2+ rise, indicating that the Ca release is mediated by activation of a Gαq-coupled receptor (Hershfinkel et al 2001;Azriel-Tamir et al 2004). The Zn 2+ -dependent Ca 2+ rise was not attenuated by an inhibitor of tyrosine kinase, suggesting that the response it is not mediated by this family of receptors.…”

mentioning

confidence: 97%

The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance

Hershfinkel

2014

Zinc Signals in Cellular Functions and Disorders

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The structural role of Zn 2+ in stabilizing numerous enzymes and zinc fingers of transcription factors has been well established for several decades. Therefore, the major effects of this metal ion on growth, development, and cognitive function were not surprising. The importance of cellular homeostasis of Zn 2+ is underlined by the identification of more than 20 proteins involved in transport of Zn 2+ into the cytoplasm and various organelles. In the past decade, evidence for a signaling role of Zn 2+ is emerging, suggesting this ion acts as a first and second messenger. Thus, transient changes in extracellular and intracellular Zn 2+ were monitored and Zn 2+ -dependent regulation of multiple signaling pathways was shown. We have identified the function of ZnR, a Gq protein-coupled receptor that triggers the release of Ca 2+ via the IP3 pathway. This ZnR-dependent signaling regulates cellular pathways involved in survival and proliferation, such as the MAP and PI3 kinase pathways, as well as modulation of ion transport systems such as the Na + /H + exchanger or the K + /Cl À co-transporter. The GPR39 was then shown to mediate extracellular Zn 2+ -dependent ZnR signaling. Here we discuss the major role of ZnR/GPR39 as the link between extracellular Zn 2+ and intracellular signaling pathways regulating the physiological function of epithelial and neuronal cells. A major future challenge will be to identify the role of ZnR/GPR39 in diseases linked to Zn 2+ dyshomeostasis.

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“…Autoaggregation of zoospores of a P. infestans transformant, that constitutively produces an active α subunit of the heterotrimeric G-protein was less affected by massetolide A (Tran, 2007) suggesting that G-protein signalling plays a role in the perception of CLPs by P. infestans Tran, 2007). Also in mammalian cells, CLPs can interfere with canonical signalling pathways by inhibiting the activity of a Gα q/11 subunit (Taniguchi et al, 2004) or a specific subclass of phospholipase C (Ui et al, 1997). In yeast, CLP treatment was found to affect phospholipid levels (Cliften et al, 1996).…”

Section: Clp-induced Responses In Phytophthoramentioning

confidence: 99%

Unraveling the Senses of Phytophthora; Leads to Novel Control Strategies?

Govers¹,

Meijer²,

Tran³

et al. 2009

Acta Hortic.

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Oomycetes cause devastating diseases on plants and animals. They cause major yield losses in many crop plants and their control heavily depends on agrochemicals. This is certainly true for the potato late blight pathogen Phytophthora infestans. Strong concerns about adverse effects of agrochemicals on food safety and environment are incentives for the development of novel, environmental friendly control strategies preferably based on natural products. Cyclic lipopeptides (CLPs) were recently discovered as a new class of natural compounds with strong activities against oomycetes including Phytophthora. CLPs lyse zoospores, inhibit mycelial growth and effectively reduce late blight disease. In order to unravel how Phytophthora senses CLPs and other environmental signals we follow two approaches. On the one hand, we monitor genome wide changes in gene expression induced by CLPs with the aim to identify the cellular pathways targeted by CLPs. On the other hand, we analyse components of ubiquitous signal transduction pathways with the aim to identify features that are unique for Phytophthora or oomycetes and, hence, could be suitable targets for novel antioomycete agents. Mining and comparing whole genome sequences have revealed that Phytophthora harbours many novel phospholipid modifying enzymes, unique for oomycetes. They have aberrant combinations of catalytic and regulatory domains occasionally combined with transmembrane domains. The latter resemble receptors that might be activated by extracellular ligands. Phospholipids, the substrates of these enzymes, are structural membrane components that also function in signalling.Together these findings open new avenues of research aimed at target-discovery in oomycetes.

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YM-254890 analogues, novel cyclic depsipeptides with Gαq/11 inhibitory activity from Chromobacterium sp. QS3666

Cited by 41 publications

References 8 publications

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance

Unraveling the Senses of Phytophthora; Leads to Novel Control Strategies?

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YM-254890 analogues, novel cyclic depsipeptides with Gαq/11 inhibitory activity from Chromobacterium sp. QS3666

Cited by 41 publications

References 8 publications

Structural basis for the specific inhibition of heterotrimeric G q protein by a small molecule

Structural basis for the specific inhibition of heterotrimeric G q protein by a small molecule

The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance

Unraveling the Senses of Phytophthora; Leads to Novel Control Strategies?

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Product

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Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule

Structural basis for the specific inhibition of heterotrimeric G _q protein by a small molecule