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1.
Dr. Sandra Liebscher Dr. Sebastian Mathea Dr. Tobias Aumüller Dr. Andreas Pech Prof. Dr. Frank Bordusa 《Chembiochem : a European journal of chemical biology》2021,22(7):1201-1204
Fluorescent fusion proteins are powerful tools for studying biological processes in living cells, but universal application is limited due to the voluminous size of those tags, which might have an impact on the folding, localization or even the biological function of the target protein. The designed biocatalyst trypsiligase enables site-directed linkage of small-sized fluorescence dyes on the N terminus of integral target proteins located in the outer membrane of living cells through a stable native peptide bond. The function of the approach was tested by using the examples of covalent derivatization of the transmembrane proteins CD147 as well as the EGF receptor, both presented on human HeLa cells. Specific trypsiligase recognition of the site of linkage was mediated by the dipeptide sequence Arg-His added to the proteins’ native N termini, pointing outside the cell membrane. The labeling procedure takes only about 5 minutes, as demonstrated for couplings of the fluorescence dye tetramethyl rhodamine and the affinity label biotin as well. 相似文献
2.
Dr. Raysa Khan Tareque Dr. Storm Hassell-Hart Dr. Tobias Krojer Dr. Anthony Bradley Dr. Srikannathasan Velupillai Dr. Romain Talon Dr. Michael Fairhead Dr. Iain J. Day Kamlesh Bala Dr. Robert Felix Dr. Paul D. Kemmitt Prof. Paul Brennan Prof. Frank von Delft Dr. Laura Díaz Sáez Prof. Kilian Huber Prof. John Spencer 《ChemMedChem》2020,15(24):2513-2520
Combined photochemical arylation, “nuisance effect” (SNAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with SNAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified. 相似文献
3.
Somatotrophs become a significant population by day 16 of chicken embryonic development. We have previously demonstrated that an earlier induction of GH cell differentiation is possible with the addition of day 16 embryonic serum to cultures of day 12 pituitary cells, an age when somatotrophs are rare. The present study was designed to identify the blood-borne signal(s) responsible for the serum activity, using reverse hemolytic plaque assays to identify individual GH-secreting cells. The activity was found to be a heat-stable, ether-soluble compound(s) that is bound or inhibited by a trypsin-sensitive protein. The extent of GH cell differentiation was greater (P < 0.05; n = 3) in response to the ether phases of heated day 16 (14.1 +/- 0.4% of all cells) and day 12 sera (9.3 +/- 0.4%) than with untreated serum from days 16 and 12 (6.1 +/- 0.4% and 0.82 +/- 0.4%, respectively). Furthermore, ether-extracted day 16 serum was more effective than ether-extracted day 12 serum, which was also different from basal (0.85 +/- 0.4%; P < 0.05). Based on this biochemical profile, the abilities of various steroids to stimulate differentiation were tested. Three steroids were found to stimulate somatotroph differentiation in vitro: 17beta-estradiol, corticosterone, and progesterone. However, the estradiol receptor antagonist, tamoxifen, while abolishing the effect of estradiol, had no effect on the induction of differentiation by day 16 serum. In contrast, RU486, a specific glucocorticoid receptor antagonist in chickens, blocked the stimulatory effects of corticosterone, progesterone, and day 16 serum on somatotroph differentiation. We next tested whether the active compound in day 16 embryonic serum was corticosterone, the predominant glucocorticoid in chickens. Incubation of day 16 serum with corticosterone antiserum, but not control antiserum, suppressed day 16 serum-induced GH cell differentiation. Therefore, we conclude that corticosterone is the blood-borne signal capable of stimulating somatotroph differentiation in vitro. The present findings together with previous reports indicate that somatotroph differentiation during embryonic development may result from an increase in circulating glucocorticoid concentrations. 相似文献
4.
Specific three- and two-disulfide intermediates that accumulate transiently during reduction of the disulfide bonds of Ca(2+)-bound bovine alpha-lactalbumin have been trapped, isolated, and characterized. The three-disulfide intermediate was shown to lack the Cys6-120 disulfide bond, confirming the observations of others. The newly-recognized two-disulfide form has been shown to lack the Cys6-120 and Cys28-111 native disulfide bonds. The remaining native disulfide bonds in the two partially reduced derivatives of alpha-lactalbumin are stable only when the proteins are in a Ca(2+)-bound state. Otherwise, they adopt an equilibrium between molten globule and unfolded conformations, and rapid thiol-disulfide interchange occurs, at a rate as high as when the proteins are fully unfolded in 8 M urea, to generate distinct mixtures of rearranged products. Urea gradient electrophoresis, circular dichroism, fluorescence, and ANS binding have been combined to give a detailed structural picture of alpha-lactalbumin, its derivatives with native and with nonnative disulfide bonds, and the fully reduced protein. The native structure of alpha-lactalbumin appears to be split by selective disulfide bond cleavage into at least one subdomain, which retains the Ca(2+)-binding site. The alpha-lactalbumin molten globule state is shown largely to result from nonspecific hydrophobic collapse, to be devoid of cooperative or specific tertiary interactions, and not to be stabilized substantially by the native or rearranged disulfide bonds. 相似文献
5.
Alpidem, an imidazopyridine that acts at the gamma-aminobutyric acid/benzodiazepine receptor complex, has been reported to be an effective anxiolytic with a more favorable side effect profile than benzodiazepines. The effect of alpidem was investigated in an 8-week, open, clinical trial in 13 patients with panic disorder, with or without agoraphobia. Three patients were responders (much improved or very much improved), five patients were nonresponders, and five patients dropped out after less than 6 weeks of treatment. Significant improvement was seen in the sample as a whole for spontaneous panic attacks, phobic avoidance, and anticipatory anxiety. Most improvement occurred during the first 4 weeks of treatment, and responders had milder panic disorder at baseline. Adverse effects were generally mild. After 8 weeks of treatment, taper of medication over 2 weeks occurred without significant worsening of panic disorder symptoms. The efficacy of alpidem in the treatment of panic disorder remains uncertain and requires assessment in a controlled trial. 相似文献
6.
Beta-COP is essential for biosynthetic membrane transport from the endoplasmic reticulum to the Golgi complex in vivo 总被引:2,自引:0,他引:2
R Pepperkok J Scheel H Horstmann HP Hauri G Griffiths TE Kreis 《Canadian Metallurgical Quarterly》1993,74(1):71-82
Experimental glomerulonephritis was induced in rats to investigate the consequence of the antigen-antibody interaction on the surface of glomerular endothelial cells (GENs). A lectin, Lens culinaris hemoagglutinin (LCH), was first planted in the left kidney by isolated perfusion of a left kidney, and then the circulation was reestablished. Rabbit anti-LCH antibodies were injected from the tail vein 3 minutes after the recirculation of the left kidney, and acute glomerulonephritis ensued. Fifteen minutes after the injection, rabbit immunoglobulin G (IgG), rat C3, and LCH were observed exclusively on the surface of GENs. Accumulation of platelets was prominent. Three hours later, the immune deposits were seen in the subendothelial space, and the polymorphonuclear cells were the dominant infiltrate in the glomeruli. Up to the seventh day, immune deposits were seen in the subendothelial space, and the widening of this area was increasingly observed. Fourteen days later, immune deposits containing rat IgG were observed in the subepithelial area, but they were only occasionally seen in the subendothelial space and in the mesangial area. No crescent formation was seen at day 14, but the mesangial area was expanded, with an increased number of cells. The number of nuclei in the cross-section of a glomerulus increased after the induction of glomerulonephritis, but the number of leukocyte common antigen-positive cells (infiltrating cells) decreased gradually from day 4 to day 14. The staining of Thy-1.1, a marker of mesangial cell, was markedly enlarged in the glomerulus at day 14. These data suggest that mesangial proliferative glomerulonephritis can be induced by the antigen-antibody interaction on the surface of GENs. 相似文献
7.
JP Horwitz I Massova TE Wiese BH Besler TH Corbett 《Canadian Metallurgical Quarterly》1994,37(6):781-786
The present study establishes correlations of in vivo growth inhibition of a solid tumor, pancreatic ductal adenocarcinoma (Panc03), of mice with the steric and electrostatic fields and the hydrophobic parameter log P of a series (32) of 1-[[2-(dialkylamino)alkyl]amino]- 9H-thioxanthen-9-ones by the 3D-QSAR method comparative molecular field analysis (CoMFA). The template molecular model was hycanthone methanesulfonate (19), the structure of which had been established previously by X-ray crystallography. The hycanthone base is protonated at the terminal nitrogen N(2), and an intramolecular hydrogen bond is present between the proximal nitrogen N(1) and carbonyl oxygen O(1) atoms. Crystallographic data also indicate a planar arrangement of bonds around N(1). However, the molecular geometry of 19, optimized by semiempirical molecular orbital methods (PM3, MNDO, AM1), showed the expected trigonal-pyramidal configuration for N(1). A comparison of MO and ab initio methods applied to a model compound, 1-amino-9H-thioxanthen-9-one, led to the selection of PM3 as the method for full geometry optimization of first the cationic and then the neutral forms of 1-32, whereas AM1 provided atomic charges for these same structures save those incorporating a sulfonamide moiety (5, 7, 20, 25, 26, 29, 31, and 32). Acceptable values for the latter were obtained from ab initio calculations. Structures were aligned by minimizing root-mean-square (rms) differences in the fitting of structures to 19 using the FIT option of SYBYL. An alternative strategy of alignment, steric and electrostatic alignment (SEAL), was invoked to provide a comparison of statistical data generated with the rms alignment. The rms-fit alignment of structures produced slightly better cross-validated and conventional r2 values than those generated with the SEAL method. In addition, the rms-fit data indicate that a shift in the lattice of one-half of its spacing has a much smaller effect on the CoMFA data for a lattice of 1 A than one of 2 A. Inclusion of log P in a CoMFA of the neutral structures effected a small (ca. 8-10%) but significant improvement in cross-validated r2 values. The relative contributions of the hydrophobic effects and the steric and electrostatic fields to the conventional r2 values were 16%, 42%, and 42%, respectively. By contrast, incorporation of frontier molecular orbital (HOMO and LUMO) energies or their gaps in the PLS analyses failed to enhance correlation coefficients derived for either the charged or uncharged compounds.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
8.
An intracellular endopeptidase was purified from cell-free extracts of Lactobacillus delbrueckii subsp. bulgaricus B14 by anion exchange chromatography on DEAE-Sepharose, hydroxyapatite chromatography, second anion exchange chromatography on Mono-Q, and metal-chelating affinity chromatography. The endopeptidase was a monomer with a molecular mass of approximately 70 kDa determined by SDS-PAGE and gel filtration. Various oligopeptides (e.g. Met-enkephalin, bradykinin) were hydrolysed by the endopeptidase. Exopeptidase activity and cleavage of dipeptides or tripeptides was not observed. The KM value for the cleavage of Metenkephalin was 1.2 mM. Temperature and pH optima were 47 °C and pH 7.7, respectively. The endopeptidase was inhibited by the classical agents for metal-dependent (EDTA) and serine (DFP) enzymes. Activity was increased by Co2+ and Mg2+, no effect was observed with Ca2+. After inhibition with EDTA, enzyme activity could be restored fully by Co2+. Activity was inhibited by Zn2+, Mn2+, Fe2+, Cu2+, Cd2+ and Hg2+. The N-terminal sequence of the endopeptidase was determined as: H2N-Val-Arg-Gly-Gly-Ser-Gly-Asp-Thr-Thr-Val-0H. 相似文献
9.
Niklas Schlimm Mirko Novakovic Robert Spielmann Tobias Knierim 《Informatik-Spektrum》2007,48(6):251-258
Nicht-funktionale Anforderungen an ein Softwaresystem beschreiben Aspekte, die nicht direkt die Funktionalit?t, wie sie der
Benutzer sieht, betreffen. 相似文献
10.
WA Schumacher CL Heran TE Steinbacher S Youssef ML Ogletree 《Canadian Metallurgical Quarterly》1993,22(4):526-533
We determined the effects of aspirin and a novel thromboxane A2/prostaglandin endoperoxide (TP)-receptor antagonist, BMS-180291, on thrombosis and bleeding times in skin and mesenteric arteries. In anesthetized rats, occlusive thrombosis was induced in the carotid artery by topical application of ferrous chloride and in the vena cava by blood flow stasis combined with either infusion of thromboplastin or hypotonic saline. Aspirin (1, 10, and 50 mg/kg) did not reduce arterial or venous thrombus weight significantly. BMS 180,291 (150 micrograms/kg/min) decreased arterial thrombus weight and hypotonic saline-induced caval thrombus weight by 58 and 57%, respectively. BMS-180291 lacked antithrombotic activity at a lower dose (50 micrograms/kg/min) and failed to inhibit thromboplastin-induced caval thrombosis. BMS-180291 (150 micrograms/kg/min) significantly reduced arterial thrombus weight by 40% when plasma epinephrine concentration was increased to 5 ng/ml. BMS-180291 and aspirin produced increases of only < or = 30% in bleeding times. These results demonstrate that BMS-180291 has antithrombotic activity in experimental aspirin-resistant arterial and venous thrombosis. Both aspirin and BMS-180291 have only modest effects on small artery hemostasis in rats. 相似文献