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451.
Kinetic evidence for tandemly arranged ligand binding sites in melanocortin 4 receptor complexes 总被引:1,自引:0,他引:1
Kopanchuk S Veiksina S Mutulis F Mutule I Yahorava S Mandrika I Petrovska R Rinken A Wikberg JE 《Neurochemistry international》2006,49(5):533-542
The melanocortin 4 receptor (MC(4)R) binding of the peptide analogue of melanocyte stimulating hormone, [(125)I]NDP-MSH, and the low molecular weight radionucleid 1-(D-1,2,3,4-tetrahydroisoquinoline-3-carboxy-D-4-(125)iodophenylalanyl)-4-cyclohexyl-4-[(1,2,4-triazol-1-yl)methyl]piperidine trifluoroacetate ([(125)I]THIQ) were compared. Kinetic analysis indicated heterogeneity in the binding of both radioligands, the binding apparently proceeding to two tandemly arranged interconnected mutually dependent binding sites. Steric considerations and BRET analysis of Rluc and GFP tagged receptors proposed that these sites are located on different subunits of receptor dimers, which form receptor complexes. According to the minimal model proposed, ligand binding proceeds consecutively to the two binding sites of the dimer. After binding of the first ligand conformational transformations of the complex occur, which is followed by binding of the second ligand. When both receptor units have bound [(125)I]NDP-MSH, the radioligand can be released only from one unit. The [(125)I]NDP-MSH bound to the remaining unit stays practically irreversibly bound due to a very slow retransformation rate of the transformed complex. The considerably faster binding of [(125)I]THIQ did not allow accurate kinetic differentiation of the two binding sites. However, addition of NDP-MSH as well as a fragment of the human agouti protein, hAGRP(83-132) to the preformed [(125)I]THIQ-MC(4)R complex drastically retarded the release of [(125)I]THIQ from the complex, blocking conformational transformations in the complex by binding into the second binding site. The consecutive binding of ligands to the MC(4)R dimers has substantial impact on the apparent ligand potencies, when determined in competition with the two different radioligands applied herein; the apparent potencies of the same ligand differing up to three orders of magnitude when assayed in competition with [(125)I]NDP-MSH or [(125)I]THIQ. 相似文献
452.
Niyomrattanakit P Yahorava S Mutule I Mutulis F Petrovska R Prusis P Katzenmeier G Wikberg JE 《The Biochemical journal》2006,397(1):203-211
The NS3 (dengue virus non-structural protein 3) serine protease of dengue virus is an essential component for virus maturation, thus representing an attractive target for the development of antiviral drugs directed at the inhibition of polyprotein processing. In the present study, we have investigated determinants of substrate specificity of the dengue virus NS3 protease by using internally quenched fluorogenic peptides containing Abz (o-aminobenzoic acid; synonymous to anthranilic acid) and 3-nitrotyrosine (nY) representing both native and chimaeric polyprotein cleavage site sequences. By using this combinatorial approach, we were able to describe the substrate preferences and determinants of specificity for the dengue virus NS2B(H)-NS3pro protease. Kinetic parameters (kcat/K(m)) for the hydrolysis of peptide substrates with systematic truncations at the prime and non-prime side revealed a length preference for peptides spanning the P4-P3' residues, and the peptide Abz-RRRRSAGnY-amide based on the dengue virus capsid protein processing site was discovered as a novel and efficient substrate of the NS3 protease (kcat/K(m)=11087 M(-1) x s(-1)). Thus, while having confirmed the exclusive preference of the NS3 protease for basic residues at the P1 and P2 positions, we have also shown that the presence of basic amino acids at the P3 and P4 positions is a major specificity-determining feature of the dengue virus NS3 protease. Investigation of the substrate peptide Abz-KKQRAGVLnY-amide based on the NS2B/NS3 polyprotein cleavage site demonstrated an unexpected high degree of cleavage efficiency. Chimaeric peptides with combinations of prime and non-prime sequences spanning the P4-P4' positions of all five native polyprotein cleavage sites revealed a preponderant effect of non-prime side residues on the K(m) values, whereas variations at the prime side sequences had higher impact on kcat. 相似文献
453.
Remoli AL Marsili G Perrotti E Gallerani E Ilari R Nappi F Cafaro A Ensoli B Gavioli R Battistini A 《The Biochemical journal》2006,396(2):371-380
454.
Javier de Vicente Robert T. Hendricks David B. Smith Jay B. Fell John Fischer Stacey R. Spencer Peter J. Stengel Peter Mohr John E. Robinson James F. Blake Ramona K. Hilgenkamp Calvin Yee George Adjabeng Todd R. Elworthy Jim Li Beihan Wang Joe T. Bamberg Seth F. Harris April Wong Vincent J.P. Leveque Robert Farrell 《Bioorganic & medicinal chemistry letters》2009,19(19):5652-5656
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure–activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue. 相似文献
455.
Javier de Vicente Robert T. Hendricks David B. Smith Jay B. Fell John Fischer Stacey R. Spencer Peter J. Stengel Peter Mohr John E. Robinson James F. Blake Ramona K. Hilgenkamp Calvin Yee Junping Zhao Todd R. Elworthy Jahari Tracy Elbert Chin Jim Li Al Lui Beihan Wang Connie Oshiro Tatyana Voronin 《Bioorganic & medicinal chemistry letters》2009,19(19):5648-5651
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core. 相似文献
456.
Sabia C de Niederhäusern S Guerrieri E Bondi M Anacarso I Iseppi R Messi P 《Current microbiology》2009,58(2):101-105
Probiotic compounds, which are often constituted of lactobacilli, exert a number of health benefits through maintenance of
the intestinal ecosystem balance. Among the important interactions that occur in the gut microbiota, plasmid transfer by mating
is an increasing cause of concern, particularly when antibiotic-resistant genes are involved. Because lactobacilli seem to
be able to influence this mechanism, the aim of the present work was to investigate the in vitro capability of two Lactobacillus plantarum strains (one bacteriocin producer and one nonproducer) to interfere with the conjugation processes. For this purpose different
matings were performed adding to the donor and recipient cells L. plantarum 35d bac+ and L. plantarum 396/1 bac– as agents of interference. Conjugations added with a Staphylococcus aureus strain or without any agent of interference were used as controls. The results of our experiments demonstrated that both
lactobacillus strains were able to decrease mating frequency. Statistically significant differences in the viable transconjugants
were obtained in the presence and in the absence of the lactobacilli. The effect was almost the same with the two L. plantarum independent of bacteriocin production. In the trial performed with S. aureus, no decrease in mating frequency was observed, confirming that the capability to interfere with R-plasmid transfer ability
could be a property of the tested L. plantarum strains. 相似文献
457.
Dorothee Dormann Ramona Rodde Dieter Edbauer Eva Bentmann Ingeborg Fischer Alexander Hruscha Manuel E Than Ian R A Mackenzie Anja Capell Bettina Schmid Manuela Neumann Christian Haass 《The EMBO journal》2010,29(16):2841-2857
Mutations in fused in sarcoma (FUS) are a cause of familial amyotrophic lateral sclerosis (fALS). Patients carrying point mutations in the C‐terminus of FUS show neuronal cytoplasmic FUS‐positive inclusions, whereas in healthy controls, FUS is predominantly nuclear. Cytoplasmic FUS inclusions have also been identified in a subset of frontotemporal lobar degeneration (FTLD‐FUS). We show that a non‐classical PY nuclear localization signal (NLS) in the C‐terminus of FUS is necessary for nuclear import. The majority of fALS‐associated mutations occur within the NLS and impair nuclear import to a degree that correlates with the age of disease onset. This presents the first case of disease‐causing mutations within a PY‐NLS. Nuclear import of FUS is dependent on Transportin, and interference with this transport pathway leads to cytoplasmic redistribution and recruitment of FUS into stress granules. Moreover, proteins known to be stress granule markers co‐deposit with inclusions in fALS and FTLD‐FUS patients, implicating stress granule formation in the pathogenesis of these diseases. We propose that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS‐opathies. 相似文献
458.
Ramona Thieme Elena Rakosy-Tican Marion Nachtigall Jörg Schubert Thilo Hammann Olga Antonova Tatjana Gavrilenko Udo Heimbach Thomas Thieme 《Plant cell reports》2010,29(10):1187-1201
Interspecific somatic hybrids between commercial cultivars of potato Solanum tuberosum L. Agave and Delikat and the wild diploid species Solanum cardiophyllum Lindl. (cph) were produced by protoplast electrofusion. The hybrid nature of the regenerated plants was confirmed by flow cytometry,
simple sequence repeat (SSR), amplified fragment length polymorphism (AFLP), microsatellite-anchored fragment length polymorphism
(MFLP) markers and morphological analysis. Somatic hybrids were assessed for their resistance to Colorado potato beetle (CPB)
using a laboratory bioassay, to Potato virus Y (PVY) by mechanical inoculation and field trials, and foliage blight in a greenhouse and by field trials. Twenty-four and
26 somatic hybrids of cph + cv. Agave or cph + cv. Delikat, respectively, showed no symptoms of infection with PVY, of which 3 and 12, respectively, were also resistant
to foliage blight. One hybrid of cph + Agave performed best in CPB and PVY resistance tests. Of the somatic hybrids that were evaluated for their morphology and
tuber yield in the field for 3 years, four did not differ significantly in tuber yield from the parental and standard cultivars.
Progeny of hybrids was obtained by pollinating them with pollen from a cultivar, selfing or cross-pollination. The results
confirm that protoplast electrofusion can be used to transfer the CPB, PVY and late blight resistance of cph into somatic hybrids. These resistant somatic hybrids can be used in pre-breeding studies, molecular characterization and
for increasing the genetic diversity available for potato breeding by marker-assisted combinatorial introgression into the
potato gene pool. 相似文献
459.
Ramona A. Robison Guy B. Kyser Kevin J. Rice Joseph M. DiTomaso 《Biological invasions》2011,13(1):35-44
Cape ivy (Delairea odorata) is a highly invasive climbing perennial vine that is primarily distributed in coastal communities of California and Oregon,
with patchy infestations in some inland riparian areas. In this study, we evaluated light as a potential environmental limitation
to the spread of Cape ivy into inland regions of the western United States. Cape ivy was collected from four locations representing
the north to south range. Plants were grown for 9 to 11 weeks in full sunlight and under two shade regimes (20 and 6% of full
sunlight). The experiment was conducted twice at two temperature regimes. Results show some within- and among-population variability,
with the southernmost San Diego County population having the highest biomass under the warmer growing conditions and the three
northern populations responding most favorably in the cooler growing conditions. Despite the minor differences within and
between populations, Cape ivy grew very poorly in full sunlight in both experiments. Although plants growing under 6% light
grew better than those in full sunlight, they were far less robust compared to plants growing at 20% light. Our results indicate
that while Cape ivy will not persist in areas with prolonged high intensity sunlight, characterized by much of the interior
regions of California and Oregon, it is expected to invade and spread in areas with reduced light, including coastal regions
frequently exposed to fog or cloudy conditions, or sub-canopy layers of riparian forests or woodlands. These communities should
be the target areas for early detection and rapid response programs to prevent further Cape ivy invasion. 相似文献
460.
We have developed a protocol to assemble in one step and one tube at least nine separate DNA fragments together into an acceptor vector, with 90% of recombinant clones obtained containing the desired construct. This protocol is based on the use of type IIs restriction enzymes and is performed by simply subjecting a mix of 10 undigested input plasmids (nine insert plasmids and the acceptor vector) to a restriction-ligation and transforming the resulting mix in competent cells. The efficiency of this protocol allows generating libraries of recombinant genes by combining in one reaction several fragment sets prepared from different parental templates. As an example, we have applied this strategy for shuffling of trypsinogen from three parental templates (bovine cationic trypsinogen, bovine anionic trypsinogen and human cationic trypsinogen) each divided in 9 separate modules. We show that one round of shuffling using the 27 trypsinogen entry plasmids can easily produce the 19,683 different possible combinations in one single restriction-ligation and that expression screening of a subset of the library allows identification of variants that can lead to higher expression levels of trypsin activity. This protocol, that we call ‘Golden Gate shuffling’, is robust, simple and efficient, can be performed with templates that have no homology, and can be combined with other shuffling protocols in order to introduce any variation in any part of a given gene. 相似文献