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961.
962.
Vergne F Bernardelli P Lorthiois E Pham N Proust E Oliveira C Mafroud AK Ducrot P Wrigglesworth R Berlioz-Seux F Coleon F Chevalier E Moreau F Idrissi M Tertre A Descours A Berna P Li M 《Bioorganic & medicinal chemistry letters》2004,14(18):4615-4621
The synthesis and optimization of pharmacokinetic parameters of structurally novel small PDE7 inhibitors is discussed. 相似文献
963.
Bernardelli P Lorthiois E Vergne F Oliveira C Mafroud AK Proust E Pham N Ducrot P Moreau F Idrissi M Tertre A Bertin B Coupe M Chevalier E Descours A Berlioz-Seux F Berna P Li M 《Bioorganic & medicinal chemistry letters》2004,14(18):4627-4631
The optimization of 5,8-disubstituted spirocyclohexane-quinazolinones into potent, selective, soluble PDE7 inhibitors with acceptable in vivo pharmacokinetic parameters is presented. 相似文献
964.
The contents and nature of the membrane lipids of Nanoarchaeum equitans and Ignicoccus sp. strain KIN4/I, grown at 90°C, and Ignicoccus sp. strain KIN4/I, cultivated at its lowest and highest growth temperatures (75°C and 95°C) were analyzed. Both organisms contained very simple and qualitatively identical assemblages of glycerol ether lipids, showing only differences in the amounts of certain components. LC–MS analyses of the total lipid extracts revealed that archaeol and caldarchaeol were the main core lipids. The predominant polar headgroups consisted of one or more sugar residues attached either directly to the core lipid or via a phosphate group. GC–MS analyses of hydrolyzed total lipid extracts revealed that the co-culture of N. equitans and Ignicoccus sp. strain KIN4/I, as well as Ignicoccus sp. strain KIN4/I grown at 90°C, contained phytane and biphytane in a ratio of approximately 4:1. Purified N. equitans cells and Ignicoccus sp. strain KIN4/I cultivated at 75°C and 95°C had a phytane to biphytane ratio of 10:1. Sugar residues were mainly mannose and small amounts of glucose. Consistent 13C fractionation patterns of isoprenoid chains of N. equitans and its host indicated that the N. equitans lipids were synthesized in the host cells. 相似文献
965.
Monti M Garolla di Bard BL Calloni G Chiti F Amoresano A Ramponi G Pucci P 《Journal of molecular biology》2004,336(1):253-262
Formation of misfolded aggregates is an essential part of what proteins can do. The process of protein aggregation is central to many human diseases and any aggregating event needs to be prevented within a cell and in protein design. In order to aggregate, a protein needs to unfold its native state, at least partially. The conformational state that is prone to aggregate is difficult to study, due to its aggregating potential and heterogeneous nature. Here, we use a systematic approach of limited proteolysis, in combination with electrospray ionisation mass spectrometry, to investigate the regions that are most flexible and solvent-exposed within the native, ligand-bound and amyloidogenic states of muscle acylphosphatase (AcP), a protein previously shown to form amyloid fibrils in the presence of trifluoroethanol. Seven proteases with different degrees of specificity have been used for this purpose. Following exposure to the aggregating conditions, a number of sites along the sequence of AcP become susceptible to proteolytic digestion. The pattern of proteolytic cleavages obtained under these conditions is considerably different from that of the native and ligand-bound conformations and includes a portion within the N-terminal tail of the protein (residues 6-7), the region of the sequence 18-23 and the position 94 near the C terminus. There is a significant overlap between the regions of the sequence found to be solvent-exposed from the present study and those previously identified to be critical in the rate-determining steps of aggregation from protein engineering approaches. This indicates that a considerable degree of solvent exposure is a feature of the portions of a protein that initiate the process of aggregation. 相似文献
966.
Edvardsen RB Lerat E Maeland AD Flåt M Tewari R Jensen MF Lehrach H Reinhardt R Seo HC Chourrout D 《Journal of molecular evolution》2004,59(4):448-457
Oikopleura dioica is a pelagic tunicate with a very small genome and a very short life cycle. In order to investigate the intron–exon organizations in Oikopleura, we have isolated and characterized ribosomal protein EF-1, Hox, and -tubulin genes. Their intron positions have been compared with those of the same genes from various invertebrates and vertebrates, including four species with entirely sequenced genomes. Oikopleura genes, like Caenorhabditis genes, have introns at a large number of nonconserved positions, which must originate from late insertions or intron sliding of ancient insertions. Both species exhibit hypervariable intron–exon organization within their -tubulin gene family. This is due to localization of most nonconserved intron positions in single members of this gene family. The hypervariability and divergence of intron positions in Oikopleura and Caenorhabditis may be related to the predominance of short introns, the processing of which is not very dependent upon the exonic environment compared to large introns. Also, both species have an undermethylated genome, and the control of methylation-induced point mutations imposes a control on exon size, at least in vertebrate genes. That introns placed at such variable positions in Oikopleura or C. elegans may serve a specific purpose is not easy to infer from our current knowledge and hypotheses on intron functions. We propose that new introns are retained in species with very short life cycles, because illegitimate exchanges including gene conversion are repressed. We also speculate that introns placed at gene-specific positions may contribute to suppressing these exchanges and thereby favor their own persistence.Supplementary material () is available for this article. 相似文献
967.
Overlapping CRE and E box motifs in the enhancer sequences of the bovine leukemia virus 5' long terminal repeat are critical for basal and acetylation-dependent transcriptional activity of the viral promoter: implications for viral latency 下载免费PDF全文
Calomme C Dekoninck A Nizet S Adam E Nguyên TL Van Den Broeke A Willems L Kettmann R Burny A Van Lint C 《Journal of virology》2004,78(24):13848-13864
968.
Members of the transglutaminase enzyme family are involved in a broad range of biological phenomena, including haemostasis, apoptosis, semen coagulation, skin formation, and wound healing. A new and rapid method for measurement of transglutaminase activity is described in this article. The enzyme links tritium-labeled putrescine to biotinylated oligoglutamine, and the tritiated peptide is bound to a streptavidin-coated microtiter plate permanently covered by a thin layer of scintillant. Only the radioisotope incorporated into the peptide substrate is close enough to the scintillant molecules for photons to be produced. The signal generation depends on the transglutaminase activity, and it can be detected by appropriate light-measuring instrumentation without separation steps. The assay is sensitive, specific, linear at concentrations of tissue transglutaminase between 0.05 and 1.6m U/ml, and suitable for high-throughput measurements. 相似文献
969.
Initiator tRNA binding by e/aIF5B, the eukaryotic/archaeal homologue of bacterial initiation factor IF2 总被引:1,自引:0,他引:1
To carry initiator Met-tRNA(i)(Met) to the small ribosomal subunit, eukaryal and archaeal cells use a heterotrimeric factor called e/aIF2. These cells also possess a homologue of bacterial IF2 called e/aIF5B. Several results indicate that the mode of action of e/aIF5B resembles some function of bacterial IF2. The e/aIF5B factor promotes the joining of ribosomal subunits. Moreover, there is genetic evidence that the factor participates in the binding of initiator tRNA to the small ribosomal subunit. However, up to now, an interaction between e/aIF5B and initiator tRNA was not evidenced. In this study, we use an assay based on protection of aminoacyl-tRNA against spontaneous deacylation to demonstrate that archaeal aIF5B indeed can interact with initiator tRNA. In complex formation, aIF5B shows specificity toward the methionyl moiety of the ligand. The complex between Saccharomyces cerevisiae eIF5B and methionylated initiator tRNA is less stable than that formed with aIF5B. In addition, this complex is almost indifferent to the side chain of the esterified amino acid. These results support the idea that, beyond the channeling of Met-tRNA(i)(Met) to the 40S subunit by e/aIF2, e/aIF5B comes to interact with initiator tRNA on the ribosome. Recognition of an aminoacylated tRNA species at this site would then allow translation to begin. In the case of archaea, this checkpoint would also include the verification of the presence of a methionine at the P site. 相似文献
970.
In Streptococcus pneumoniae, an H103Y substitution in the ATP binding site of the ParE subunit of topoisomerase IV was shown to confer quinolone resistance and hypersensitivity to novobiocin when associated with an S84F change in the A subunit of DNA gyrase. We reconstituted in vitro the wild-type topoisomerase IV and its ParE mutant. The ParE mutant enzyme showed a decreased activity for decatenation at subsaturating ATP levels and was more sensitive to inhibition by novobiocin but was as sensitive to quinolones. These results show that the ParE alteration H103Y alone is not responsible for quinolone resistance and agree with the assumption that it facilitates the open conformation of the ATP binding site that would lead to novobiocin hypersensitivity and to a higher requirement of ATP. 相似文献