Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Rational design of inhibitors of VirA-VirG two-component signal transduction.

ABSTRACT: VirA-VirG two-component system regulates the vir (virulence) operon in response to specific host factors (xenognosins) in the plant pathogen Agrobacterium tumefaciens. Using whole cell assays, stable inhibitors inspired by the labile natural benzoxazinone inhibitor HDMBOA are developed. It is found that aromatic aldehydes represent a minimal structural unit for activity. In particular, 3-hydroxy-4,6-dimethoxy-3H-isobenzofuran-1-one (HDI) was found to have the highest activity, making it the most potent developed inhibitor of virulence gene expression in Agrobacterium.

SUBMITTER: Maresh J

PROVIDER: S-EPMC2806187 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Rational design of inhibitors of VirA-VirG two-component signal transduction.

Maresh Justin J Zhang Jin J Tzeng Yih-Ling YL Goodman Nora A NA Lynn David G DG

Bioorganic & medicinal chemistry letters 20070410 12

VirA-VirG two-component system regulates the vir (virulence) operon in response to specific host factors (xenognosins) in the plant pathogen Agrobacterium tumefaciens. Using whole cell assays, stable inhibitors inspired by the labile natural benzoxazinone inhibitor HDMBOA are developed. It is found that aromatic aldehydes represent a minimal structural unit for activity. In particular, 3-hydroxy-4,6-dimethoxy-3H-isobenzofuran-1-one (HDI) was found to have the highest activity, making it the most ...[more]

PMID: 17470391

Similar Datasets

Auxiliary phosphatases in two-component signal transduction.

Project description:Signal termination in two-component systems occurs by loss of the phosphoryl group from the response regulator protein. This review explores our current understanding of the structures, catalytic mechanisms and means of regulation of the known families of phosphatases that catalyze response regulator dephosphorylation. The CheZ and CheC/CheX/FliY families, despite different overall structures, employ identical catalytic strategies using an amide side chain to orient a water molecule for in-line attack of the aspartyl phosphate. Spo0E phosphatases contain sequence and structural features that suggest a strategy similar to the chemotaxis phosphatases but the mechanism used by the Rap phosphatases is not yet elucidated. Identification of features shared by phosphatase families may aid in the identification of currently unrecognized classes of response regulator phosphatases.

| S-EPMC2862455 | biostudies-literature

Molecular Mechanisms of Two-Component Signal Transduction.

Project description:Two-component systems (TCS) comprising sensor histidine kinases and response regulator proteins are among the most important players in bacterial and archaeal signal transduction and also occur in reduced numbers in some eukaryotic organisms. Given their importance to cellular survival, virulence, and cellular development, these systems are among the most scrutinized bacterial proteins. In the recent years, a flurry of bioinformatics, genetic, biochemical, and structural studies have provided detailed insights into many molecular mechanisms that underlie the detection of signals and the generation of the appropriate response by TCS. Importantly, it has become clear that there is significant diversity in the mechanisms employed by individual systems. This review discusses the current knowledge on common themes and divergences from the paradigm of TCS signaling. An emphasis is on the information gained by a flurry of recent structural and bioinformatics studies.

| S-EPMC5023499 | biostudies-literature

Two-component signal transduction systems in Streptomyces and related organisms

Project description:Two component sensor-response regulator systems (TCSs) are very common in the genomes of the Streptomyces species that have been fully sequenced to date. It has been suggested that this large number is an evolutionary response to the variable environment that Streptomyces encounter in soil. Notwithstanding this, TCSs are also more common in the sequenced genomes of other Actinomycetales when these are compared to the genomes of most other eubacteria. In this study, we have used DNA/DNA genome microarray analysis to compare fourteen Streptomyces species and one closely related genus to Streptomyces coelicolor in order to identify a core group of such systems. This core group is compared to the syntenous and non-syntenous TCSs present in the genome sequences of other Actinomycetales in order to separate the systems into those present in Actinomycetales in general, the Streptomyces specific systems and the species specific systems. Horizontal transfer does not seem to play a very important role in the evolution of the TCS complement analyzed in this study. However, cognate pairs do not necessarily seem to evolve at the same pace, which may indicate the evolutionary responses to environmental variation may be reflected differently in sequence changes within the two components of the TCSs. The overall analysis allowed subclassification of the orphan TCSs and the TCS cognate pairs and identification of possible targets for further study using gene knockouts, gene overexpression, reporter genes and yeast two hybrid analysis.

2009-01-31 | GSE13621 | GEO

Rewiring the specificity of two-component signal transduction systems.

Project description:Two-component signal transduction systems are the predominant means by which bacteria sense and respond to environmental stimuli. Bacteria often employ tens or hundreds of these paralogous signaling systems, comprised of histidine kinases (HKs) and their cognate response regulators (RRs). Faithful transmission of information through these signaling pathways and avoidance of detrimental crosstalk demand exquisite specificity of HK-RR interactions. To identify the determinants of two-component signaling specificity, we examined patterns of amino acid coevolution in large, multiple sequence alignments of cognate kinase-regulator pairs. Guided by these results, we demonstrate that a subset of the coevolving residues is sufficient, when mutated, to completely switch the substrate specificity of the kinase EnvZ. Our results shed light on the basis of molecular discrimination in two-component signaling pathways, provide a general approach for the rational rewiring of these pathways, and suggest that analyses of coevolution may facilitate the reprogramming of other signaling systems and protein-protein interactions.

| S-EPMC2453690 | biostudies-literature

Two-component signal transduction systems in Streptomyces and related organisms

2010-06-24 | E-GEOD-13621 | biostudies-arrayexpress

Histidine phosphotransfer proteins in fungal two-component signal transduction pathways.

Project description:The histidine phosphotransfer (HPt) protein Ypd1 is an important participant in the Saccharomyces cerevisiae multistep two-component signal transduction pathway and, unlike the expanded histidine kinase gene family, is encoded by a single gene in nearly all model and pathogenic fungi. Ypd1 is essential for viability in both S. cerevisiae and in Cryptococcus neoformans. These and other aspects of Ypd1 biology, combined with the availability of structural and mutational data in S. cerevisiae, suggest that the essential interactions between Ypd1 and response regulator domains would be a good target for antifungal drug development. The goal of this minireview is to summarize the wealth of data on S. cerevisiae Ypd1 and to consider the potential benefits of conducting related studies in pathogenic fungi.

| S-EPMC3754533 | biostudies-literature

Hysteretic and graded responses in bacterial two-component signal transduction.

Project description:Bacterial two-component systems (TCS) are key signal transduction networks regulating global responses to environmental change. Environmental signals may modulate the phosphorylation state of sensor kinases (SK). The phosphorylated SK transfers the phosphate to its cognate response regulator (RR), which causes physiological response to the signal. Frequently, the SK is bifunctional and, when unphosphorylated, it is also capable of dephosphorylating the RR. The phosphatase activity may also be modulated by environmental signals. Using the EnvZ/OmpR system as an example, we constructed mathematical models to examine the steady-state and kinetic properties of the network. Mathematical modelling reveals that the TCS can show bistable behaviour for a given range of parameter values if unphosphorylated SK and RR form a dead-end complex that prevents SK autophosphorylation. Additionally, for bistability to exist the major dephosphorylation flux of the RR must not depend on the unphosphorylated SK. Structural modelling and published affinity studies suggest that the unphosphorylated SK EnvZ and the RR OmpR form a dead-end complex. However, bistability is not possible because the dephosphorylation of OmpR approximately P is mainly done by unphosphorylated EnvZ. The implications of this potential bistability in the design of the EnvZ/OmpR network and other TCS are discussed.

| S-EPMC4372536 | biostudies-literature

A Moraxella catarrhalis two-component signal transduction system necessary for growth in liquid media affects production of two lysozyme inhibitors.

Project description:There are a paucity of data concerning gene products that could contribute to the ability of Moraxella catarrhalis to colonize the human nasopharynx. Inactivation of a gene (mesR) encoding a predicted response regulator of a two-component signal transduction system in M. catarrhalis yielded a mutant unable to grow in liquid media. This mesR mutant also exhibited increased sensitivity to certain stressors, including polymyxin B, SDS, and hydrogen peroxide. Inactivation of the gene (mesS) encoding the predicted cognate sensor (histidine) kinase yielded a mutant with the same inability to grow in liquid media as the mesR mutant. DNA microarray and real-time reverse transcriptase PCR analyses indicated that several genes previously shown to be involved in the ability of M. catarrhalis to persist in the chinchilla nasopharynx were upregulated in the mesR mutant. Two other open reading frames upregulated in the mesR mutant were shown to encode small proteins (LipA and LipB) that had amino acid sequence homology to bacterial adhesins and structural homology to bacterial lysozyme inhibitors. Inactivation of both lipA and lipB did not affect the ability of M. catarrhalis O35E to attach to a human bronchial epithelial cell line in vitro. Purified recombinant LipA and LipB fusion proteins were each shown to inhibit human lysozyme activity in vitro and in saliva. A lipA lipB deletion mutant was more sensitive than the wild-type parent strain to killing by human lysozyme in the presence of human apolactoferrin. This is the first report of the production of lysozyme inhibitors by M. catarrhalis.

| S-EPMC4288865 | biostudies-literature

Investigation of pneumococcal two-component signal transduction system RR/HK06 in TIGR4

Project description:We wanted to identify genes regulated by the two-component signal transduction system RR/HK06 in Streptococcus pneumoniae. We used microarray in order to discover regulated genes, investigating the effects of the over-expression of RR06 in TIGR4 (serotype 4). Keywords: Gene Regulation

2006-12-17 | GSE5330 | GEO

Investigation of pneumococcal two-component signal transduction system RR/HK06 in D39

2006-12-23 | GSE5322 | GEO