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1.
Models for the spatial distribution of protein, lipid and water in gap junction structures have been constructed from the results of the analysis of X-ray diffraction data described here and the electron microscope and chemical data presented in the preceding paper (Caspar, D. L. D., D. A. Goodenough, L. Makowski, and W.C. Phillips. 1977. 74:605-628). The continuous intensity distribution on the meridian of the X-ray diffraction pattern was measured, and corrected for the effects of the partially ordered stacking and partial orientation of the junctions in the X-ray specimens. The electron density distribution in the direction perpendicular to the plane of the junction was calculated from the meridional intensity data. Determination of the interference function for the stacking of the junctions improved the accuracy of the electron density profile. The pair-correlation function, which provides information about the packing of junctions in the specimen, was calculated from the interference function. The intensities of the hexagonal lattice reflections on the equator of the X-ray pattern were used in coordination with the electron microscope data to calculate to the two-dimensional electron density projection onto the plane of the membrane. Differences in the structure of the connexons as seen in the meridional profile and equatorial projections were shown to be correlated to changes in lattice constant. The parts of the junction structure which are variable have been distinguished from the invariant parts by comparison of the X-ray data from different specimens. The combination of these results with electron microscope and chemical data provides low resolution three- dimensional representations of the structures of gap junctions. 相似文献
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DeFeo-Jones D Garsky VM Wong BK Feng DM Bolyar T Haskell K Kiefer DM Leander K McAvoy E Lumma P Wai J Senderak ET Motzel SL Keenan K Van Zwieten M Lin JH Freidinger R Huff J Oliff A Jones RE 《Nature medicine》2000,6(11):1248-1252
We covalently linked doxorubicin with a peptide that is hydrolyzable by prostate-specific antigen. In the presence of prostate tumor cells secreting prostate-specific antigen, the peptide moiety of this conjugate, L-377,202, was hydrolyzed, resulting in the release of leucine-doxorubicin and doxorubicin, which are both very cytotoxic to cancer cells. However, L-377,202 was much less cytotoxic than conventional doxorubicin to cells in culture that do not secrete prostate-specific antigen. L-377,202 was approximately 15 times more effective than was conventional doxorubicin at inhibiting the growth of human prostate cancer tumors in nude mice when both drugs were used at their maximally tolerated doses. Nude mice inoculated with human prostate tumor cells secreting prostate-specific antigen showed considerable reductions in tumor burden with minimal total body weight loss when treated with L-377, 202. This improvement in therapeutic index correlated with the selective localization of leucine-doxorubicin and free doxorubicin in tissues secreting prostate-specific antigen after exposure to L-377,202. 相似文献
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Tucker TJ Abrams MT Buser CA Davide JP Ellis-Hutchings M Fernandes C Gibbs JB Graham SL Hartman GD Huber HE Liu D Lobell RB Lumma WC Robinson RG Sisko JT Smith AM 《Bioorganic & medicinal chemistry letters》2002,12(15):2027-2030
We have prepared a series of potent, dual inhibitors of the prenyl transferases farnesyl protein transferase (FPTase) and geranyl-geranyl protein transferase I (GGPTase). The compounds were shown to possess potent activity against both enzymes in cell culture. Mechanistic analysis has shown that the compounds are CAAX competitive for FPTase inhibition but geranyl-geranyl pyrophosphate (GGPP) competitive for GGPTase inhibiton. 相似文献
5.
The role of nitric oxide in cancer 总被引:4,自引:0,他引:4
WEIMING XU Li ZHI LIU MARILENA LOIZIDOU MOHAMED AHMED IAN G CHARLES Wolfson Institute for Biomedical Research Cruciform Building Gower Street UCL London WC E AUUK Department of Surgery Charles Bell House - Riding House Street UCL London WW EJ UK 《Cell research》2002,(Z2)
Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including va-sodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interestingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic pro 相似文献
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Paired sequence difference in ribosomal RNAs: evolutionary and phylogenetic implications 总被引:12,自引:1,他引:11
Ribosomal RNAs have secondary structures that are maintained by internal
Watson-Crick pairing. Through analysis of chordate, arthropod, and plant 5S
ribosomal RNA sequences, we show that Darwinian selection operates on these
nucleotide sequences to maintain functionally important secondary
structure. Insect phylogenies based on nucleotide positions involved in
pairing and the production of secondary structure are incongruent with
those constructed on the basis of positions that are not. Furthermore,
phylogeny reconstruction using these nonpairing bases is concordant with
other, morphological data.
相似文献
8.
Mitochondrial gene order is not conserved in arthropods: prostriate and metastriate tick mitochondrial genomes 总被引:25,自引:15,他引:10
The entire mitochondrial genome was sequenced in a prostriate tick, Ixodes
hexagonus, and a metastriate tick, Rhipicephalus sanguineus. Both genomes
encode 22 tRNAs, 13 proteins, and two ribosomal RNAs. Prostriate ticks are
basal members of Ixodidae and have the same gene order as Limulus
polyphemus. In contrast, in R. sanguineus, a block of genes encoding NADH
dehydrogenase subunit 1 (ND1), tRNA(Leu)(UUR), tRNA(Leu)(CUN), 16S rDNA,
tRNA(Val), 12S rDNA, the control region, and the tRNA(Ile) and tRNA(Gln)
have translocated to a position between the tRNA(Glu) and tRNA(Phe) genes.
The tRNA(Cys) gene has translocated between the control region and the
tRNA(Met) gene, and the tRNA(Leu)(CUN) gene has translocated between the
tRNA(Ser)(UCN) gene and the control region. Furthermore, the control region
is duplicated, and both copies undergo concerted evolution. Primers that
flank these rearrangements confirm that this gene order is conserved in all
metastriate ticks examined. Correspondence analysis of amino acid and codon
use in the two ticks and in nine other arthropod mitochondrial genomes
indicate a strong bias in R. sanguineus towards amino acids encoded by
AT-rich codons.
相似文献
9.
Huber HE Robinson RG Watkins A Nahas DD Abrams MT Buser CA Lobell RB Patrick D Anthony NJ Dinsmore CJ Graham SL Hartman GD Lumma WC Williams TM Heimbrook DC 《The Journal of biological chemistry》2001,276(27):24457-24465
We have identified and characterized potent and specific inhibitors of geranylgeranyl-protein transferase type I (GGPTase I), as well as dual inhibitors of GGPTase I and farnesyl-protein transferase. Many of these inhibitors require the presence of phosphate anions for maximum activity against GGPTase I in vitro. Inhibitors with a strong anion dependence were competitive with geranylgeranyl pyrophosphate (GGPP), rather than with the peptide substrate, which had served as the original template for inhibitor design. One of the most effective anions was ATP, which at low millimolar concentrations increased the potency of GGPTase I inhibitors up to several hundred-fold. In the case of clinical candidate l-778,123, this increase in potency was shown to result from two major interactions: competitive binding of inhibitor and GGPP, and competitive binding of ATP and GGPP. At 5 mm, ATP caused an increase in the apparent K(d) for the GGPP-GGPTase I interaction from 20 pm to 4 nm, resulting in correspondingly tighter inhibitor binding. A subset of very potent GGPP-competitive inhibitors displayed slow tight binding to GGPTase I with apparent on and off rates on the order of 10(6) m(-)1 s(-)1 and 10(-)3 s(-)1, respectively. Slow binding and the anion requirement suggest that these inhibitors may act as transition state analogs. After accounting for anion requirement, slow binding, and mechanism of competition, the structure-activity relationship determined in vitro correlated well with the inhibition of processing of GGPTase I substrate Rap1a in vivo. 相似文献
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