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71.
Young WB Sprengeler P Shrader WD Li Y Rai R Verner E Jenkins T Fatheree P Kolesnikov A Janc JW Cregar L Elrod K Katz B 《Bioorganic & medicinal chemistry letters》2006,16(3):710-713
Inhibition of coagulation proteases such as thrombin, fXa, and fVIIa has been a focus of ongoing research to produce safe and effective antithrombotic agents. Herein, we describe a unique zinc-mediated chelation strategy to streamline the discovery of potent inhibitors of fIIa, fXa, and fVIIa. SAR studies that led to the development of selective inhibitors of fXa will also be detailed. 相似文献
72.
Shrader WD Kolesnikov A Burgess-Henry J Rai R Hendrix J Hu H Torkelson S Ton T Young WB Katz BA Yu C Tang J Cabuslay R Sanford E Janc JW Sprengeler PA 《Bioorganic & medicinal chemistry letters》2006,16(6):1596-1600
Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa. 相似文献
73.
Maureen E. Estevez Alexander V. Kolesnikov Petri Ala-Laurila Rosalie K. Crouch Victor I. Govardovskii M. Carter Cornwall 《The Journal of general physiology》2009,134(2):137-150
Cone photoreceptors of the vertebrate retina terminate their response to light much faster than rod photoreceptors. However, the molecular mechanisms underlying this rapid response termination in cones are poorly understood. The experiments presented here tested two related hypotheses: first, that the rapid decay rate of metarhodopsin (Meta) II in red-sensitive cones depends on interactions between the 9-methyl group of retinal and the opsin part of the pigment molecule, and second, that rapid Meta II decay is critical for rapid recovery from saturation of red-sensitive cones after exposure to bright light. Microspectrophotometric measurements of pigment photolysis, microfluorometric measurements of retinol production, and single-cell electrophysiological recordings of flash responses of salamander cones were performed to test these hypotheses. In all cases, cones were bleached and their visual pigment was regenerated with either 11-cis retinal or with 11-cis 9-demethyl retinal, an analogue of retinal lacking the 9-methyl group. Meta II decay was four to five times slower and subsequent retinol production was three to four times slower in red-sensitive cones lacking the 9-methyl group of retinal. This was accompanied by a significant slowing of the recovery from saturation in cones lacking the 9-methyl group after exposure to bright (>0.1% visual pigment photoactivated) but not dim light. A mathematical model of the turn-off process of phototransduction revealed that the slower recovery of photoresponse can be explained by slower Meta decay of 9-demethyl visual pigment. These results demonstrate that the 9-methyl group of retinal is required for steric chromophore–opsin interactions that favor both the rapid decay of Meta II and the rapid response recovery after exposure to bright light in red-sensitive cones. 相似文献
74.
Kritsky MS Telegina TA Vechtomova YL Kolesnikov MP Lyudnikova TA Golub OA 《Biochemistry. Biokhimii?a》2010,75(10):1200-1216
Excited flavin and pterin molecules are active in intermolecular energy transfer and in photocatalysis of redox reactions
resulting in conservation of free energy. Flavin-containing pigments produced in models of the prebiotic environment are capable
of converting photon energy into the energy of phosphoanhydride bonds of ATP. However, during evolution photochemical reactions
involving excited FMN or FAD molecules failed to become participants of bioenergy transfer systems, but they appear in enzymes
responsible for repair of UV-damaged DNA (DNA photolyases) and also in receptors of blue and UV-A light regulating vital functions
of organisms. The families of these photoproteins (DNA-photolyases and cryptochromes, LOV-domain- and BLUF-domain-containing
proteins) are different in the structure and in mechanisms of the photoprocesses. The excited flavin molecules are involved
in photochemical processes in reaction centers of these photoproteins. In DNA photolyases and cryptochromes the excitation
energy on the reaction center flavin is supplied from an antenna molecule that is bound with the same polypeptide. The role
of antenna is played by MTHF or by 8-HDF in some DNA photolyases, i.e. also by molecules with known coenzyme functions in
biocatalysis. Differences in the structure of chromophore-binding domains suggest an independent origin of the photoprotein
families. The analysis of structure and properties of coenzyme molecules reveals some specific features that were significant
in evolution for their being selected as chromophores in these proteins. 相似文献
75.
The spatial distribution of two marmot species Marmota baibacina and M. sibirica in a zone of coexistence was studied by using their alarm call as a diagnostic trait. It was found that M. baibacina prefers to inhabit bouldery screes, whereas M. sibirica inhabits all suitable biotopes. The difference in biotopic distribution of these species could be explained by M. sibirica forcing M. baibacina out of optimum habitats. Cases of coexistence of both species in one family group sites were registered, which might contribute
to the appearance of hybrids. 相似文献
76.
The effect of ATP, GTP and cAMP on the cGMP-dependent conductance of the fragments from frog rod plasma membrane 总被引:1,自引:0,他引:1
G N Filatov A B Jainazarov S S Kolesnikov A L Lyubarsky E E Fesenko 《FEBS letters》1989,245(1-2):185-188
Using a 'patch-clamp' method in the 'inside-out' configuration, ATP, ADP, AMP-PCP and AMP-PNP have been shown to increase the cGMP-dependent component of the rod plasma membrane conductance 2-4-fold and GTP, GDP but not GMP or nonhydrolyzable GTP analogs GMP-PNP and GTP-gamma-S to abolish the ATP action. The ATP and GTP effects were observed at [EDTA] = 1 mM when magnesium and calcium ions were absent. In about half of the experiments the cGMP-dependent conductance was shown to be increased by cAMP in the micromolar concentration range by 10-50%, the cAMP action did not depend on the presence of nucleoside triphosphates. In vivo ATP, GTP and cAMP are assumed to modulate the sensitivity of the photoreceptor plasma membrane to cGMP. 相似文献
77.
The populations of mykizha Parasalmo (O.) mykiss from western and eastern coasts of Kamchatka were studied by restriction analysis of a fragment of fish mitochondrial genome that included the control region and the region of the cytochrome b gene (cytb). The restriction patterns obtained with five enzymes (MspI; Tru1I; RsaI; BsuRI; DdeI) were identical in all studied individuals. Sequencing of the cytb gene showed high similarity between all samples (99.6-100%). In general, the geographical group of mykiss from Kamchatka is monophyletic with low genetic divergence at the population level. Shantarian mykiss originates most likely from that native to Kamchatka. 相似文献
78.
Efficient system for producing the recombinant Fab of DNA-hydrolyzing antibody BV04-01 in metylotrophic yeast Pichia pastoris was developed. Addition of peptides encompassing the Jun-Fos leucine zipper at the C-termini of the antibody chains facilitated the in vivo assembling of the Fab. The yield of secreted functionally active BV04-01 Fab was about 3 mg/L. Catalytic efficiency of supercoiled DNA hydrolysis by the Fab obtained was 1.8 x 10(6) M(-1) min(-1). 相似文献
79.
The peculiarities of antioxidant system functioning of duck organism were exposed in postnatal ontogenesis. The liver tissues and blood plasma of daily ducks are characterized by high LPO level, that leads to changes of superoxide dismutase, catalase, glutathione peroxidase activity. The level of LPO products declines, but disforming of adapt mechanism breaks the coordinating function of enzymes while vitamin A and E provision are deficient sience 7 till 42 days age. In the 8 and 10 ontogenesis weeks the LPO intensification depends on lipid content increase. Perhaps, it is a response on energy need growth of duck organism in forming feather period. 相似文献
80.
The BCL-xL and ACR-1 Genes Promote Differentiation and Reduce Apoptosis in Muscle Fibers of mdx Mice
V. M. Mikhailov A. V. Kropotov A. V. Zelenin R. I. Krutilina V. A. Kolesnikov I. A. Zelenina A. N. Baranov G. I. Stein O. V. Ostapenko N. V. Tomilin V. S. Baranov 《Russian Journal of Genetics》2002,38(11):1221-1225
The effects of the human BCL-xL and ACR-1genes on dystrophin expression in cross-striated muscle fibers (CSMF) and on CSMF viability were studied in mdx mice after ballistic cotransfection with the human dystrophin minigene. In control mice, the proportion of dystrophin-positive (D(+)) and dying CSMF were 2.1 ± 0.1 and 2.1 ± 0.3%, respectively. Introduction of the dystrophin minigene (20 g of the pSG5dys plasmid) increased the proportions of D(+) and dying CSMF to 5.6 ± 1.4% and 4.5 ± 0.9%, respectively. When pSG5dys was introduced along with the pSFFV-Neo plasmid carrying the BCL-xL gene (10 g of each plasmid per shot), the death of CSMF decreased to 3.7 ± 1% and the proportion of D(+) CSMF significantly (P < 0.05) increased to 12.2 ± 2.2%. Cotransfection with the dystrophin minigene and the BCL-xL gene at 20 g of each plasmid per shot did not stimulate generation of D(+) CSMF, but did reduce the CSMF death to 1.5 ± 0.3%. Introduction of pSG5dys along with the pRc-CMV-10.1 plasmid containing the ACR-1 gene (10 g of each plasmid per shot) reduced the proportion of D(+) CSMF to 1.1 ± 0.5% and significantly reduced the proportion of dying CSMF to 0.9 ± 0.3% as compared with the proportions observed in intact mice or in mice subjected to transfection with pSG5dys. Introduction of the pSG5dys plasmid substantially reduced the proportion of CSMF with peripheral nuclei, suggesting disturbed CSMF differentiation. After cotransfection with the human dystrophin minigene, the BCL-xL and ACR-1 genes did not affect the extent of CSMF differentiation as compared with that observed in the case of the dystrophin minigene alone. Thus, ballistic transfection of mdx mice with the human dystrophin gene used along with the BCL-xLor ACR-1 gene was shown to suppress the death of muscle fibers and to expedite dystrophin synthesis and cell differentiation. 相似文献