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91.
Robarge MJ Bom DC Tumey LN Varga N Gleason E Silver D Song J Murphy SM Ekema G Doucette C Hanniford D Palmer M Pawlowski G Danzig J Loftus M Hunady K Sherf BA Mays RW Stricker-Krongrad A Brunden KR Harrington JJ Bennani YL 《Bioorganic & medicinal chemistry letters》2005,15(6):1749-1753
The chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH-2), also found on eosinophils and basophils, is a prostaglandin D2 receptor involved in the recruitment of these cell types during an inflammatory response. In this report, we describe the synthesis and optimization of a ramatroban isostere that is a selective and potent antagonist of CRTH-2 which may be useful in the treatment of certain diseases. 相似文献
92.
Sándor Z Varga A Horváth P Nagy B Szolcsányi J 《Cellular & molecular biology letters》2005,10(3):499-514
We constructed and analyzed a new cell line called HT5-1, which stably expresses an enhanced green fluorescent protein-tagged version of the rat vanilloid receptor 1 (VR1/TRPV1). The fluorescent receptor allowed easy measurement of receptor expression and expression level-based purification of cells via fluorescence-activated cell sorting. The HT5-1 cell line was compared to cells transiently transfected with the fluorescent receptor, to cells expressing the native rat vanilloid receptor, and to isolated capsaicin-sensitive rat trigeminal sensory neurons. Fura-2 microfluorimetry measurements of the calcium influx upon capsaicin induction showed that, by contrast to transiently transfected cells, HT5-1 cells respond uniformly to the stimulation, due to the similar level of receptor expression in individual cells. HT5-1 cells showed similar behaviour to isolated trigeminal root ganglion neurons, including marked tachyphylaxis upon repeated capsaicin induction, and a lack of calcium ion release from intracellular storage sites. 相似文献
93.
The influence of the product inhibition by dihydroxyacetone (DHA) on Gluconobacter oxydans for a novel semi-continuous two-stage repeated-fed-batch process was examined quantitatively. It was shown that the culture
was able to grow up to a DHA concentration of 80 kg m−3 without any influence of product inhibition. The regeneration capability of the reversibly product inhibited culture from
a laboratory-scale bioreactor system was observed up to a DHA concentration of about 160 kg m−3. At higher DHA concentrations, the culture was irreversibly product inhibited. However, due to the robust membrane-bound
glycerol dehydrogenase of G. oxydans, product formation was still active for a prolonged period of time. The reachable maximum final DHA concentration was as
high as 220 kg m−3. The lag phases for growth increased exponentially with increasing DHA threshold values of the first reactor stage. These
results correlated well with fluorescence in situ hybridization (FISH) measurements confirming that the number of active cells
decreased exponentially with increasing DHA concentrations. 相似文献
94.
Jurkuvenaite A Varga K Nowotarski K Kirk KL Sorscher EJ Li Y Clancy JP Bebok Z Collawn JF 《The Journal of biological chemistry》2006,281(6):3329-3334
Efficient endocytosis of the cystic fibrosis transmembrane conductance regulator (CFTR) is mediated by a tyrosine-based internalization signal in the CFTR carboxyl-terminal tail 1424YDSI1427. In the present studies, two naturally occurring cystic fibrosis mutations in the amino terminus of CFTR, R31C, and R31L were examined. To determine the defect that these mutations cause, the Arg-31 mutants were expressed in COS-7 cells and their biogenesis and trafficking to the cell surface tested in metabolic pulse-chase and surface biotinylation assays, respectively. The results indicated that both Arg-31 mutants were processed to band C at approximately 50% the efficiency of the wild-type protein. However, once processed and delivered to the cell surface, their half-lives were the same as wild-type protein. Interestingly, indirect immunofluorescence and cell surface biotinylation indicated that the surface pool was much smaller than could be accounted for based on the biogenesis defect alone. Therefore, the Arg-31 mutants were tested in internalization assays and found to be internalized at 2x the rate of the wild-type protein. Patch clamp and 6-methoxy-N-(3-sulfopropyl)quinolinium analysis confirmed reduced amounts of functional Arg-31 channels at the cell surface. Together, the results suggest that both R31C and R31L mutations compromise biogenesis and enhance internalization of CFTR. These two additive effects contribute to the loss of surface expression and the associated defect in chloride conductance that is consistent with a disease phenotype. 相似文献
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98.
Varga A Flachner B Konarev P Gráczer E Szabó J Svergun D Závodszky P Vas M 《FEBS letters》2006,580(11):2698-2706
Closure of the two domains of 3-phosphoglycerate kinase, upon substrate binding, is essential for the enzyme function. The available crystal structures cannot provide sufficient information about the mechanism of substrate assisted domain closure and about the requirement of only one or both substrates, since lattice forces may hinder the large scale domain movements. In this study the known X-ray data, obtained for the open and closed conformations, were probed by solution small-angle X-ray scattering experiments. The results prove that binding of both substrates is essential for domain closure. Molecular graphical analysis, indeed, reveals formation of a double-sided H-bond network, which affects substantially the shape of the main molecular hinge at beta-strand L, under the concerted action of both substrates. 相似文献
99.
The microtubule cytoskeleton and the mitotic spindle are highly dynamic structures, yet their sizes are remarkably constant, thus indicating that the growth and shrinkage of their constituent microtubules are finely balanced. This balance is achieved, in part, through kinesin-8 proteins (such as Kip3p in budding yeast and KLP67A in Drosophila) that destabilize microtubules. Here, we directly demonstrate that Kip3p destabilizes microtubules by depolymerizing them--accounting for the effects of kinesin-8 perturbations on microtubule and spindle length observed in fungi and metazoan cells. Furthermore, using single-molecule microscopy assays, we show that Kip3p has several properties that distinguish it from other depolymerizing kinesins, such as the kinesin-13 MCAK. First, Kip3p disassembles microtubules exclusively at the plus end and second, remarkably, Kip3p depolymerizes longer microtubules faster than shorter ones. These properties are consequences of Kip3p being a highly processive, plus-end-directed motor, both in vitro and in vivo. Length-dependent depolymerization provides a new mechanism for controlling the lengths of subcellular structures. 相似文献
100.
Wang X Saludes JP Zhao TX Csakai A Fiorini Z Chavez SA Li J Lee GI Varga K Yin H 《Biochimica et biophysica acta》2012,1818(9):2282-2289
The lateral transmembrane protein-protein interaction has been regarded as "undruggable" despite its importance in many biological processes. The homo-trimerization of transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) is critical for the constitutive oncogenic activation of the Epstein-Barr virus (EBV). Herein, we report a small molecule agent, NSC 259242 (compound 1), to be a TMD-5 self-association disruptor. Both the positively charged acetimidamide functional groups and the stilbene backbone of compound 1 are essential for its inhibitory activity. Furthermore, cell-based assays revealed that compound 1 inhibits full-length LMP-1 signaling in EBV infected B cells. These studies demonstrated a new strategy for identifying small molecule disruptors for investigating transmembrane protein-protein interactions. 相似文献