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591.
Forouhar F Huang WN Liu JH Chien KY Wu WG Hsiao CD 《The Journal of biological chemistry》2003,278(24):21980-21988
Cobra cardiotoxins (CTXs) have previously been shown to induce membrane fusion of vesicles formed by phospholipids such as cardiolipin or sphingomyelin. CTX can also form a pore in membrane bilayers containing a anionic lipid such as phosphatidylserine or phosphatidylglycerol. Herein, we show that the interaction of CTX with negatively charged lipids causes CTX dimerization, an important intermediate for the eventual oligomerization of CTX during the CTX-induced fusion and pore formation process. The structural basis of the lipid-induced oligomerization of CTX A3, a major CTX from Naja atra, is then illustrated by the crystal structure of CTX A3 in complex with SDS; SDS likely mimics anionic lipids of the membrane under micelle conditions at 1.9-A resolution. The crystal packing reveals distinct SDS-free and SDS-rich regions; in the latter two types of interconnecting CTX A3 dimers, D1 and D2, and several SDS molecules can be identified to stabilize D1 and D2 by simultaneously interacting with residues at each dimer interface. When the three CTXSDS complexes in the asymmetric unit are overlaid, the orientation of CTX A3 monomers relative to the SDS molecules in the crystal is strikingly similar to that of the toxin with respect to model membranes as determined by NMR and Fourier transform infrared methods. These results not only illustrate how lipid-induced CTX dimer formation may be transformed into oligomers either as inverted micelles of fusion intermediates or as membrane pore of anionic lipid bilayers but also underscore a potential role for SDS in x-ray diffraction study of protein-membrane interactions in the future. 相似文献
592.
Zangeneh F Basu R Shah P Arora P Camilleri M Rizza RA 《American journal of physiology. Endocrinology and metabolism》2003,285(2):E280-E286
Portal infusion of glucose at rates approximating endogenous glucose production (EGP) causes paradoxical hypoglycemia in wild-type but not GLUT2 null mice, implying activation of a specific portal glucose sensor. To determine whether this occurs in humans, glucose containing [3-3H]glucose was infused intraduodenally at rates of 3.1 mg. kg-1. min-1 (n = 5), 1.55 mg. kg-1. min-1 (n = 9), or 0/0.1 mg. kg-1. min-1 (n = 9) for 7 h in healthy nondiabetic subjects. [6,6-2H2]glucose was infused intravenously to enable simultaneous measurement of EGP, glucose disappearance, and the rate of appearance of the intraduodenally infused glucose. Plasma glucose concentrations fell (P < 0.01) from 90 +/- 1 to 84 +/- 2 mg/dl during the 0/0.1 mg. kg-1. min-1 id infusions but increased (P < 0.001) to 104 +/- 5 and 107 +/- 3 mg/dl, respectively, during the 1.55 and 3.1 mg. kg-1. min-1 id infusions. In contrast, insulin increased (P < 0.05) during the 1.55 and 3.0 mg. kg-1. min-1 infusions, reaching a peak of 10 +/- 2 and 18 +/- 5 micro U/ml, respectively, by 2 h. Insulin concentrations then fell back to concentrations that no longer differed by study end (7 +/- 1 vs. 8 +/- 1 micro U/ml). This resulted in comparable suppression of EGP by study end (0.84 +/- 0.2 and 0.63 +/- 0.1 mg. kg-1. min-1). Glucose disappearance was higher (P < 0.01) during the final hour of the 3.1 than 1.55 mg. kg-1. min-1 id infusion (4.47 +/- 0.2 vs. 2.6 +/- 0.1 mg. kg-1. min-1), likely because of the slightly, but not significantly, higher glucose and insulin concentrations. We conclude that, in contrast to mice, selective portal glucose delivery at rates approximating EGP does not cause hypoglycemia in humans. 相似文献
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Le Borgne M Marchand P Le Baut G Ahmadi M Smith HJ Nicholls PJ 《Journal of enzyme inhibition and medicinal chemistry》2003,18(2):155-158
Among a library of 70 azoles, 8 indole derivatives substituted in the 2-, 3- or 5- position with an azolylmethyl or alpha-azolylbenzyl chain were evaluated for retinoic acid (RA) metabolism inhibitory activity. The most active inhibitors identified in this study were 5-bromo-1-ethyl-3-methyl-2-[(phenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-indole (3) (68.9% inhibition) and 5-bromo-1-ethyl-2-[(4-fluorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-3-methyl-1H-indole (6) (60.4% inhibition). At the same concentration (100 microM) ketoconazole exerted similar inhibitory effect (70% inhibition). 相似文献
595.
The existence of nonrandom patterns in codon assignments is supported by many statistical and biochemical studies. The canonical genetic code is known to be highly efficient in minimizing the effects of mistranslation errors and point mutations. For example, it is known that when an error induces the conversion of an amino acid to another, the biochemical properties of the resulting amino acid are usually very similar to that of the original. Prior studies include many attempts at quantitative estimation of the fraction of randomly generated codes which, based upon load minimization, score higher than the canonical genetic code. In this study, we took into consideration both the relative frequencies of amino acids and nonsense mistranslations, factors which had been previously ignored. Incorporation of these parameters, resulted in a fitness function (phi) which rendered the canonical genetic code to be highly optimized with respect to load minimization. Considering termination codons, we applied a biosynthetic version of the coevolution theory, however, with low significance. We employed a revised cost for the precursor-product pairs of amino acids and showed that the significance of this approach depends on the cost measure matrix used by the researcher. Thus, we have compared the two prominent matrices, point accepted mutations 74-100 (PAM(74-100)) and mutation matrix in our study. 相似文献
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Anti‐angiogenic effects of CD73‐specific siRNA‐loaded nanoparticles in breast cancer‐bearing mice 下载免费PDF全文