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91.
A selection of 1-amino-substituted beta-carbolines have been prepared by amination of 1-chloro-beta-carboline as simple mimics of manzamine A and chloroquine and their intercalating ability, anticancer and antimalarial activity were studied. 相似文献
92.
Walters I Bennion C Connolly S Croshaw PJ Hardy K Hartopp P Jackson CG King SJ Lawrence L Mete A Murray D Robinson DH Stein L Wells E John Withnall W 《Bioorganic & medicinal chemistry letters》2004,14(14):3645-3649
The high lipophilicity of a series of cytosolic phospholipase A(2) inhibitors has been reduced by the modification of a decyloxyphenyl chain designed to mimic the arachidonyl group of the natural substrate. These changes have resulted in an improvement in the whole cell potency of the inhibitors. 相似文献
93.
Petosa C Schoehn G Askjaer P Bauer U Moulin M Steuerwald U Soler-López M Baudin F Mattaj IW Müller CW 《Molecular cell》2004,16(5):761-775
CRM1/Exportin1 mediates the nuclear export of proteins bearing a leucine-rich nuclear export signal (NES) by forming a cooperative ternary complex with the NES-bearing substrate and the small GTPase Ran. We present a structural model of human CRM1 based on a combination of X-ray crystallography, homology modeling, and electron microscopy. The architecture of CRM1 resembles that of the import receptor transportin1, with 19 HEAT repeats and a large loop implicated in Ran binding. Residues critical for NES recognition are identified adjacent to the cysteine residue targeted by leptomycin B (LMB), a specific CRM1 inhibitor. We present evidence that a conformational change of the Ran binding loop accounts for the cooperativity of Ran- and substrate binding and for the selective enhancement of CRM1-mediated export by the cofactor RanBP3. Our findings indicate that a single architectural and mechanistic framework can explain the divergent effects of RanGTP on substrate binding by many import and export receptors. 相似文献
94.
Mitotic chromosomes must be organised into a highly ordered and compacted form to allow proper segregation of DNA during each round of cell division. Two new studies report observations of DNA compaction by eukaryotic and bacterial condensin molecules in real time using magnetic and optical trapping micromanipulation techniques. 相似文献
95.
Integrins are essential receptors for the development and functioning of multicellular animals because they mediate cell migration and cell adhesion, and regulate cell proliferation and apoptosis. Cellular regulation of the affinity of integrins for ligands - so-called 'integrin activation' - is a central property of these receptors. Integrin activation controls cell adhesion, migration and extracellular matrix assembly, thereby contributing to processes such as angiogenesis, tumor cell metastasis, inflammation, the immune response and hemostasis. Recent studies indicate that a crucial, final step in integrin activation is the binding of talin, a cytoskeletal protein, to the cytoplasmic domain of the integrin beta subunit. These results provide a focus for unraveling the many biochemical pathways implicated in integrin activation and suggest a general structural model for the connections between integrins and diverse cellular signal transduction pathways. 相似文献
96.
Zhang Z Feige JN Chang AB Anderson IJ Brodianski VM Vitreschak AG Gelfand MS Saier MH 《Archives of microbiology》2003,180(2):88-100
An ABC-type transporter in Escherichia coli that transports both l- and d-methionine, but not other natural amino acids, was identified. This system is the first functionally characterized member of a novel family of bacterial permeases within the ABC superfamily. This family was designated the methionine uptake transporter (MUT) family (TC #3.A.1.23). The proteins that comprise the transporters of this family were analyzed phylogenetically, revealing the probable existence of several sequence-divergent primordial paralogues, no more than two of which have been transmitted to any currently sequenced organism. In addition, MetJ, the pleiotropic methionine repressor protein, was shown to negatively control expression of the operon encoding the ABC-type methionine uptake system. The identification of MetJ binding sites (in gram-negative bacteria) or S-boxes (in gram-positive bacteria) in the promoter regions of several MUT transporter-encoding operons suggests that many MUT family members transport organic sulfur compounds. Electronic Supplementary Material Supplementary material is available for this article if you access the article at . A link in the frame on the left on that page takes you directly to the supplementary material. 相似文献
97.
Wilson RJ Rangachari K Saldanha JW Rickman L Buxton RS Eccleston JF 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2003,358(1429):155-62; discussion 162-4
Malaria and related parasites retain a vestigial, but biosynthetically active, plastid organelle acquired far back in evolution from a red algal cell. The organelle appears to be essential for parasite transmission from cell to cell and carries the smallest known plastid genome. Why has this genome been retained? The genes it carries seem to be dedicated to the expression of just two "housekeeping" genes. We speculate that one of these, called ycf24 in plants and sufB in bacteria, is tied to an essential "dark" reaction of the organelle--fatty acid biosynthesis. "Ball-park" clues to the function of bacterial suf genes have emerged only recently and point to the areas of iron homeostasis, [Fe-S] cluster formation and oxidative stress. We present experimental evidence for a physical interaction between SufB and its putative partner SufC (ycf16). In both malaria and plants, SufC is encoded in the nucleus and specifies an ATPase that is imported into the plastid. 相似文献
98.
T cells infiltrate the brain in murine and human transmissible spongiform encephalopathies
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Lewicki H Tishon A Homann D Mazarguil H Laval F Asensio VC Campbell IL DeArmond S Coon B Teng C Gairin JE Oldstone MB 《Journal of virology》2003,77(6):3799-3808
CD4 and CD8 T lymphocytes infiltrate the parenchyma of mouse brains several weeks after intracerebral, intraperitoneal, or oral inoculation with the Chandler strain of mouse scrapie, a pattern not seen with inoculation of prion protein knockout (PrP(-/-)) mice. Associated with this cellular infiltration are expression of MHC class I and II molecules and elevation in levels of the T-cell chemokines, especially macrophage inflammatory protein 1beta, IFN-gamma-inducible protein 10, and RANTES. T cells were also found in the central nervous system (CNS) in five of six patients with Creutzfeldt-Jakob disease. T cells harvested from brains and spleens of scrapie-infected mice were analyzed using a newly identified mouse PrP (mPrP) peptide bearing the canonical binding motifs to major histocompatibility complex (MHC) class I H-2(b) or H-2(d) molecules, appropriate MHC class I tetramers made to include these peptides, and CD4 and CD8 T cells stimulated with 15-mer overlapping peptides covering the whole mPrP. Minimal to modest K(b) tetramer binding of mPrP amino acids (aa) 2 to 9, aa 152 to 160, and aa 232 to 241 was observed, but such tetramer-binding lymphocytes as well as CD4 and CD8 lymphocytes incubated with the full repertoire of mPrP peptides failed to synthesize intracellular gamma interferon (IFN-gamma) or tumor necrosis factor alpha (TNF-alpha) cytokines and were unable to lyse PrP(-/-) embryo fibroblasts or macrophages coated with (51)Cr-labeled mPrP peptide. These results suggest that the expression of PrP(sc) in the CNS is associated with release of chemokines and, as shown previously, cytokines that attract and retain PrP-activated T cells and, quite likely, bystander activated T cells that have migrated from the periphery into the CNS. However, these CD4 and CD8 T cells are defective in such an effector function(s) as IFN-gamma and TNF-alpha expression or release or lytic activity. 相似文献
99.
Sharpe IA Thomas L Loughnan M Motin L Palant E Croker DE Alewood D Chen S Graham RM Alewood PF Adams DJ Lewis RJ 《The Journal of biological chemistry》2003,278(36):34451-34457
A peptide contained in the venom of the predatory marine snail Conus tulipa, rho-TIA, has previously been shown to possess alpha1-adrenoreceptor antagonist activity. Here, we further characterize its pharmacological activity as well as its structure-activity relationships. In the isolated rat vas deferens, rho-TIA inhibited alpha1-adrenoreceptor-mediated increases in cytosolic Ca2+ concentration that were triggered by norepinephrine, but did not affect presynaptic alpha2-adrenoreceptor-mediated responses. In radioligand binding assays using [125I]HEAT, rho-TIA displayed slightly greater potency at the alpha 1B than at the alpha 1A or alpha 1D subtypes. Moreover, although it did not affect the rate of association for [3H]prazosin binding to the alpha 1B-adrenoreceptor, the dissociation rate was increased, indicating non-competitive antagonism by rho-TIA. N-terminally truncated analogs of rho-TIA were less active than the full-length peptide, with a large decline in activity observed upon removal of the fourth residue of rho-TIA (Arg4). An alanine walk of rho-TIA confirmed the importance of Arg4 for activity and revealed a number of other residues clustered around Arg4 that contribute to the potency of rho-TIA. The unique allosteric antagonism of rho-TIA resulting from its interaction with receptor residues that constitute a binding site that is distinct from that of the classical competitive alpha1-adrenoreceptor antagonists may allow the development of inhibitors that are highly subtype selective. 相似文献
100.
The stromal cell-derived factor-1alpha/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas 总被引:4,自引:0,他引:4
Kayali AG Van Gunst K Campbell IL Stotland A Kritzik M Liu G Flodström-Tullberg M Zhang YQ Sarvetnick N 《The Journal of cell biology》2003,163(4):859-869
The SDF-1alpha/CXCR4 ligand/chemokine receptor pair is required for appropriate patterning during ontogeny and stimulates the growth and differentiation of critical cell types. Here, we demonstrate SDF-1alpha and CXCR4 expression in fetal pancreas. We have found that SDF-1alpha and its receptor CXCR4 are expressed in islets, also CXCR4 is expressed in and around the proliferating duct epithelium of the regenerating pancreas of the interferon (IFN) gamma-nonobese diabetic mouse. We show that SDF-1alpha stimulates the phosphorylation of Akt, mitogen-activated protein kinase, and Src in pancreatic duct cells. Furthermore, migration assays indicate a stimulatory effect of SDF-1alpha on ductal cell migration. Importantly, blocking the SDF-1alpha/CXCR4 axis in IFNgamma-nonobese diabetic mice resulted in diminished proliferation and increased apoptosis in the pancreatic ductal cells. Together, these data indicate that the SDF-1alpha-CXCR4 ligand receptor axis is an obligatory component in the maintenance of duct cell survival, proliferation, and migration during pancreatic regeneration. 相似文献