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821.
822.
Wiener JJ Gomez L Venkatesan H Santillán A Allison BD Schwarz KL Shinde S Tang L Hack MD Morrow BJ Motley ST Goldschmidt RM Shaw KJ Jones TK Grice CA 《Bioorganic & medicinal chemistry letters》2007,17(10):2718-2722
We have previously reported a novel class of tetrahydroindazoles that display potency against a variety of Gram-positive and Gram-negative bacteria, potentially via interaction with type II bacterial topoisomerases. Herein are reported SAR investigations of this new series. Several compounds possessing broad-spectrum potency were prepared. Further, these compounds exhibit activity against multidrug-resistant Gram-positive microorganisms equivalent to that against susceptible strains. 相似文献
823.
Thermal transitions in human very-low-density lipoprotein: fusion, rupture, and dissociation of HDL-like particles 总被引:1,自引:0,他引:1
Very-low-density lipoproteins (VLDL) are metabolic precursors of low-density lipoproteins (LDL) and a risk factor for atherosclerosis. Human VLDL are heterogeneous complexes containing a triacylglycerol-rich apolar lipid core and polar surface composed of phospholipids, a nonexchangeable apolipoprotein B, and exchangeable apolipoproteins E and Cs. We report the first stability study of VLDL. Circular dichroism and turbidity data reveal an irreversible heat-induced VLDL transition that involves formation of larger particles and repacking of apolar lipids but no global protein unfolding. Heating rate effect on the melting temperature indicates a kinetically controlled reaction with high activation energy, Ea. Arrhenius analysis of the turbidity data reveals two kinetic phases with Ea = 53 +/- 7 kcal/mol that correspond to distinct morphological transitions observed by electron microscopy. One transition involves VLDL fusion, partial rupture, and dissociation of small spherical particles (d = 7-15 nm), and another involves complete lipoprotein disintegration and lipid coalescence into droplets accompanied by dissociation of apolipoprotein B. The small particles, which are unique to VLDL denaturation, are comparable in size and density to high-density lipoproteins (HDL); they have an apolar lipid core and polar surface composed of exchangeable apolipoproteins (E and possibly Cs) and phospholipids. We conclude that, similar to HDL and LDL, VLDL are stabilized by kinetic barriers that prevent particle fusion and rupture and decelerate spontaneous interconversion among lipoprotein classes and subclasses. In addition to fusion, VLDL disruption involves transient formation of HDL-like particles that may mimic protein exchange among VLDL and HDL pools in plasma. 相似文献
824.
Cloning and Transfer of the Salmonella Pathogenicity Island 2 Type III Secretion System for Studies of a Range of Gram-Negative Genera
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The engineering of bacterial strains with specific phenotypes frequently requires the use of blocks or “cassettes” of genes that act together to perform a desired function. The potential benefits of utilizing type III secretion systems in this regard are becoming increasingly realized since these systems can be used to direct interactions with host cells for beneficial purposes such as vaccine development, anticancer therapies, and targeted protein delivery. However, convenient methods to clone and transfer type III secretion systems for studies of a range of different types of bacteria are lacking. In addition to functional applications, such methods would also reveal important information about the evolution of a given type III secretion system, such as its ability to be expressed and functional outside of the strain of origin. We describe here the cloning of the Salmonella enterica serovar Typhimurium pathogenicity island 2 (SPI-2) type III secretion system onto a vector that can be easily transferred to a range of gram-negative bacterial genera. We found that expression of the cloned SPI-2 system in different Gammaproteobacteria and Alphaproteobacteria (as monitored by SseB protein levels) is dependent on the bacterial strain and growth medium. We also demonstrate that the cloned system is functional for secretion, can direct interactions with macrophages, and can be used as a novel tool to analyze the predicted interaction of SseB with host cells. This work provides a foundation for future applications where the cloned SPI-2 region (or other cloned type III systems) can provide a desired function to an engineered gram-negative strain. 相似文献
825.
The N-terminus of Dictyostelium Scar interacts with Abi and HSPC300 and is essential for proper regulation and function 总被引:1,自引:0,他引:1
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Scar/WAVE proteins, members of the conserved Wiskott-Aldrich syndrome (WAS) family, promote actin polymerization by activating the Arp2/3 complex. A number of proteins, including a complex containing Nap1, PIR121, Abi1/2, and HSPC300, interact with Scar/WAVE, though the role of this complex in regulating Scar function remains unclear. Here we identify a short N-terminal region of Dictyostelium Scar that is necessary and sufficient for interaction with HSPC300 and Abi in vitro. Cells expressing Scar lacking this N-terminal region show abnormalities in F-actin distribution, cell morphology, movement, and cytokinesis. This is true even in the presence of wild-type Scar. The data suggest that the first 96 amino acids of Scar are necessary for participation in a large-molecular-weight protein complex, and that this Scar-containing complex is responsible for the proper localization and regulation of Scar. The presence of mis-regulated or unregulated Scar has significant deleterious effects on cells and may explain the need to keep Scar activity tightly controlled in vivo either by assembly in a complex or by rapid degradation. 相似文献
826.
827.
Xiao‐Bo Wang Chih‐Ming Hsu Jos C. B. Dubeux Cheryl Mackowiak Ann Blount Xing‐Guo Han Hui‐Ling Liao 《Ecology and evolution》2019,9(22):12676-12687
There is a growing awareness of the importance of soil microorganisms in agricultural management practices. Currently, much less is known about whether different crop cultivar has an effect on the taxonomic structure and diversity, and specific functions of soil bacterial communities. Here, we examined the changes of the diversity and composition and enzyme‐encoding nitrogenase genes in a long‐term field experiment with seven different rhizoma peanut cultivars in southeastern USA, coupling high‐throughput 16S rRNA gene sequencing and the sequence‐based function prediction with Tax4Fun. Of the 32 phyla detected (Proteobacteria class), 13 were dominant: Acidobacteria, Alphaproteobacteria, Actinobacteria, Betaproteobacteria, Bacteroidetes, Verrucomicrobia, Gammaproteobacteria, Deltaproteobacteria, Gemmatimonadetes, Firmicutes, Nitrospirae, Chloroflexi, and Planctomycetes (relative abundance >1%). We found no evidence that the diversity and composition of bacterial communities were significantly different among different cultivars, but the abundance of some dominant bacterial groups that have N‐fixation potentials (at broad or fine taxonomic level) and predicted abundances of some enzyme‐encoding nitrogenase genes showed significant across‐cultivar differences. The nitrogenase genes were notably abundant in Florigraze and Latitude soils while remarkably lower in Arbook and UF_TITO soils when compared with other cultivars, indicating different nitrogen fixation potentials among different cultivars. The findings also suggest that the abundance of certain bacterial taxa and the specific function bacteria perform in ecosystems can have an inherent association. Our study is helpful to understand how microbiological responses and feedback to different plant genotypes through the variation in structure and function of their communities in the rhizosphere. 相似文献
828.
829.
830.
Hannah Nguyen Abdellah Allali-Hassani Stephen Antonysamy Shawn Chang Lisa Hong Chen Carmen Curtis Spencer Emtage Li Fan Tarun Gheyi Fengling Li Shichong Liu Joseph R. Martin David Mendel Jonathan B. Olsen Laura Pelletier Tatiana Shatseva Song Wu Feiyu Fred Zhang Cheryl H. Arrowsmith Peter J. Brown Robert M. Campbell Benjamin A. Garcia Dalia Barsyte-Lovejoy Mary Mader Masoud Vedadi 《The Journal of biological chemistry》2015,290(22):13641-13653
SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary carcinomas, and that overexpression correlates with poor patient survival. However, the mechanism(s) by which SMYD2 promotes oncogenesis is not understood. A small molecule probe for SMYD2 would allow for the pharmacological dissection of this biology. In this report, we disclose LLY-507, a cell-active, potent small molecule inhibitor of SMYD2. LLY-507 is >100-fold selective for SMYD2 over a broad range of methyltransferase and non-methyltransferase targets. A 1.63-Å resolution crystal structure of SMYD2 in complex with LLY-507 shows the inhibitor binding in the substrate peptide binding pocket. LLY-507 is active in cells as measured by reduction of SMYD2-induced monomethylation of p53 Lys370 at submicromolar concentrations. We used LLY-507 to further test other potential roles of SMYD2. Mass spectrometry-based proteomics showed that cellular global histone methylation levels were not significantly affected by SMYD2 inhibition with LLY-507, and subcellular fractionation studies indicate that SMYD2 is primarily cytoplasmic, suggesting that SMYD2 targets a very small subset of histones at specific chromatin loci and/or non-histone substrates. Breast and liver cancers were identified through in silico data mining as tumor types that display amplification and/or overexpression of SMYD2. LLY-507 inhibited the proliferation of several esophageal, liver, and breast cancer cell lines in a dose-dependent manner. These findings suggest that LLY-507 serves as a valuable chemical probe to aid in the dissection of SMYD2 function in cancer and other biological processes. 相似文献