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91.
The activity of DNA polymerase I from Saccharomyces cerevisiae is inhibited, in a dose-dependent fashion, by the oncogenic beta-blocker 1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1305) and by the non-oncogenic beta-blockers 1-(2-nitro-5-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (ZAMI 1327), atenolol, and propranolol, the latter having the highest inhibiting activity. The inhibition is due to an interaction of the beta-blockers with the free enzyme and with the enzyme-DNA complex. The degree of inhibition is directly related to the hydrophobicity of the aromatic moiety and to the length and hydrophilicity of the aliphatic chain of the inhibitor. No relation seems to exist between the in vitro inhibition of yeast DNA polymerase I by beta-blockers and their oncogenic activity. 相似文献
92.
93.
A method of determining the water structure in protein crystals is described using neutron solvent difference maps. These maps are obtained by comparing the changes in diffracted intensities between two data sets, one in which H2O is the major solvent constituent, and a second in which D2O is the solvent medium. To a good first approximation, the protein atom contributions to the scattering intensities in both data sets are equal and cancel, but since H2O and D2O have very different neutron-scattering properties, their differences are accentuated to reveal an accurate representation of the solvent structure. The method also employs a series of density modification steps that impose known physical constraints on the density distribution function in the unit cell by making real space modifications directly to the density maps. Important attributes of the method are that (1) it is less subjective in the assignment of water positions than X-ray analysis; (2) there is threefold improvement in the signal-to-noise ratio for the solvent density; and (3) the iterative density modification produces a low-biased representation of the solvent density. Tests showed that water molecules with as low as 10% occupancy could be confidently assigned. About 300 water sites were assigned for trypsin from the refined solvent density; 140 of these sites were defined in the maps as discrete peaks, while the remaining were found within less-ordered channels of density. There is a very good correspondence between the sites in the primary hydration layer and waters found in the X-ray structure. Most water sites are clustered into H-bonding networks, many of which are found along intermolecular contact zones. The bound water is equally distributed between contacting apolar and polar atoms at the protein interface. A common occurrence at hydrophobic surfaces is that apolar atoms are circumvented by one or more waters that are part of a larger water network. When the effects on surface accessibility by neighboring molecules in the crystal lattice are taken into consideration, only about 29% of the surface does not interface ordered water. About 25% of the ordered water is found in the second hydration sphere. In many instances these waters bridge larger clusters of primary layer waters. It is apparent that, in certain regions of the crystal, the organization of ordered water reflects the characteristics of the crystal environment more than those of trypsin's surface alone. 相似文献
94.
High resolution analysis of functional determinants on human tissue-type plasminogen activator 总被引:18,自引:0,他引:18
W F Bennett N F Paoni B A Keyt D Botstein A J Jones L Presta F M Wurm M J Zoller 《The Journal of biological chemistry》1991,266(8):5191-5201
Sixty-four variants of human tissue-type plasminogen activator (tPA) were produced using recombinant DNA techniques. Charged residues were converted to alanine in clusters of from one to four changes per variant; these clusters spanned all the domains of the molecule. The variants were expressed by mammalian cells and were analyzed for a variety of properties. Variants of tPA were found that had reduced activity with respect to each tested property; in a few cases increased activity was observed. Analysis of these effects prompted the following conclusions: 1) charged residues in the nonprotease domains are less involved in fibrin stimulation of tPA activity than those in the protease domain, and it is possible to increase the fibrin specificity (i.e. the stimulation of tPA activity by fibrin compared to fibrinogen) by mutations at several sites in the protease domain; 2) the difference in enzymatic activity between the one- and two-chain forms of tPA can be increased by mutations at several sites on the protease domain; 3) binding of tPA to lysine-Sepharose was affected only by mutations to kringle-2, whereas binding to fibrin was affected most by mutations in the other domains; 4) clot lysis was influenced by mutations in all domains except kringle-2; 5) sensitivity to plasminogen activator inhibitor-1 seems to reside exclusively in the region surrounding residue 300. A model of the tPA protease domain has been used to map some of the critical residues and regions. 相似文献
95.
Pagano K Torella R Foglieni C Bugatti A Tomaselli S Zetta L Presta M Rusnati M Taraboletti G Colombo G Ragona L 《PloS one》2012,7(5):e36990
Fibroblast growth factors (FGFs) are recognized targets for the development of therapies against angiogenesis-driven diseases, including cancer. The formation of a ternary complex with the transmembrane tyrosine kinase receptors (FGFRs), and heparan sulphate proteoglycans (HSPGs) is required for FGF2 pro-angiogenic activity. Here by using a combination of techniques including Nuclear Magnetic Resonance, Molecular Dynamics, Surface Plasmon Resonance and cell-based binding assays we clarify the molecular mechanism of inhibition of an angiostatic small molecule, sm27, mimicking the endogenous inhibitor of angiogenesis, thrombospondin-1. NMR and MD data demonstrate that sm27 engages the heparin-binding site of FGF2 and induces long-range dynamics perturbations along FGF2/FGFR1 interface regions. The functional consequence of the inhibitor binding is an impaired FGF2 interaction with both its receptors, as demonstrated by SPR and cell-based binding assays. We propose that sm27 antiangiogenic activity is based on a twofold-direct and allosteric-mechanism, inhibiting FGF2 binding to both its receptors. 相似文献
96.
Dallanora AF Grasel CE Heine CP Demarco FF Pereira-Cenci T Presta AA Boscato N 《Gerodontology》2012,29(2):e865-e869
doi: 10.1111/j.1741‐2358.2011.00574.x Prevalence of temporomandibular disorders in a population of complete denture wearers Background: Complete tooth loss among the elderly is still frequent in developing countries and the incidence of temporomandibular disorders (TMD) is a common finding in complete denture wearers. Objectives: The aim of this study was to evaluate the prevalence of temporomandibular disorders (TMD) in a population of complete denture wearers. Materials and Methods: The data were collected by four examiners for the diagnosis of use and need for complete dentures followed by the World Health Organization standards and interviews for TMD signs and symptoms evaluation. Exploratory variables included demographic, socio‐economic status and TMD prevalence. Results: The prevalence of TMD among denture wearers was 55.12%. Chi‐squared test showed no statistical difference between subjects with or without TMD for gender, geographical location and skin colour (p < 0.05). The number of subjects with TMD increased as the period of complete denture wear increased, although no statistical difference between groups were found (p < 0.05). Conclusions: There is a need of educational programmes aiming at the importance of health care and periodical change of a complete denture, and strategies with a preventive approach to quality general dental care. 相似文献
97.
98.
GA Bray 《Obesity (Silver Spring, Md.)》1997,5(3):271-274
It is often difficult to identify the ‘who, when, and where’ of advances in medicine and surgery because it's a rare advance indeed (such as the use of digitalis by William Withering) that can be clearly related to the astuteness of one person at one time and place. 相似文献
99.
SÉBASTIEN VILLÉGER GAËL GRENOUILLET VIRGINIE SUC SÉBASTIEN BROSSE 《Freshwater Biology》2012,57(11):2330-2341
1. We measured N and P excretion rates of 470 individuals belonging to 18 freshwater fish species widespread in Western Europe. We assessed the effect of body mass on excretion rates at both the intra‐ and interspecific levels. 2. The high variability in per capita N and P excretion rates was mainly determined by differences in body mass. The scaling coefficients of allometric relationships for both N and P excretion rates were significantly lower than 1 (mean ± SE, 0.95 ± 0.04 and 0.81 ± 0.05, respectively). 3. The slope of the allometric relationship between fish mass and nutrient excretion rate was significantly different among species. We did not detect any influence of phylogenetic conservatism on fish mass and on excretion rates. Further investigations are needed to understand the biological determinants of these differences. 4. This high intra‐ and interspecific variability in per capita excretion rates, coupled with differences in fish body mass, produce marked differences in biomass‐standardised excretion rates. These results thus indicate the necessity for further experimental and in situ investigations on the consequences of nutrient recycling by fish in freshwater ecosystems. 相似文献
100.
Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc 总被引:10,自引:0,他引:10
Idusogie EE Presta LG Gazzano-Santoro H Totpal K Wong PY Ultsch M Meng YG Mulkerrin MG 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(8):4178-4184
Rituxan (Rituximab) is a chimeric mAb with human IgG1 constant domains used in the therapy of non-Hodgkin's B cell lymphomas. This Ab targets B cells by binding to the cell-surface receptor, CD20. In our investigation of the mechanism of B cell depletion mediated by Rituximab, we first constructed mutants of Rituximab defective in complement activation but with all other effector functions intact. Our results demonstrate that the previously described C1q binding motif in murine IgG2b constituting residues E318, K320, and K322 is not applicable to a human IgG1 when challenged with either human, rabbit, or guinea pig complement. Alanine substitution at positions E318 and K320 in Rituximab had little or no effect on C1q binding and complement activation, whereas alanine substitution at positions D270, K322, P329, and P331 significantly reduced the ability of Rituximab to bind C1q and activate complement. We have also observed that concentrations of complement approaching physiological levels are able to rescue >60% of the activity of these mutant Abs with low affinity for C1q. These data localize the C1q binding epicenter on human IgG1 and suggest that there are species-specific differences in the C1q binding site of Igs. 相似文献