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Andre Kiryanov Srinivasa Natala Benjamin Jones Christopher McBride Victoria Feher Betty Lam Yan Liu Kouhei Honda Noriko Uchiyama Tomohiro Kawamoto Yuichi Hikichi Lilly Zhang David Hosfield Robert Skene Hua Zou Jeffrey Stafford Xiaodong Cao Takashi Ichikawa 《Bioorganic & medicinal chemistry letters》2017,27(5):1311-1315
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model. 相似文献
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Evolution at the tip and base of the X chromosome in an African population of Drosophila melanogaster 总被引:1,自引:0,他引:1
Hitchhiking effects of advantageous mutations have been invoked to explain
reduced polymorphism in regions of low crossing-over in Drosophila. Besides
reducing DNA heterozygosity, hitchhiking effects should produce strong
linkage disequilibrium and a frequency spectrum skewed toward an excess of
rare polymorphisms (compared to the neutral expectation). We measured DNA
polymorphism in a Zimbabwe population of D. melanogaster at three loci,
yellow, achaete, and suppressor of forked, located in regions of reduced
crossing-over. Similar to previously published surveys of these genomic
regions in other populations, we observed low levels of nucleotide
variability. However, the frequency spectrum was compatible with a neutral
model, and there was abundant evidence for recombination in the history of
the yellow and ac genes. Thus, some aspects of the data cannot be accounted
for by a simple hitchhiking model. An alternative hypothesis, background
selection, might be compatible with the observed patterns of linkage
disequilibrium and the frequency spectrum. However, this model cannot
account for the observed reduction in nucleotide heterozygosity. Thus,
there is currently no satisfactory theoretical model for the data from the
tip and base of the X chromosome in D. melanogaster.
相似文献
35.
Oligogalacturonic acids (OGAs), derived from plant cell wall pectin, have
been implicated in a number of signal transduction pathways involved in
growth, development and defense responses of higher plants. This study
investigates the size range of OGAs capable of inducing ethylene synthesis
in tomato plants, and demonstrates that in contrast with many other
effects, only short chain OGAs are active. Oligomers across a range of DP
from 2-15 were separated and purified to homogeneity by QAE-Sephadex anion
exchange chromatography using a novel elution system. The OGAs were applied
to tomato plants and assayed for their ability to induce ethylene gas
release and changes in steady state levels of mRNA encoding the ethylene
forming enzyme aminocyclopropane-1-carboxylic acid oxidase (ACO). The study
demonstrated that only OGAs in the size range of DP4-6 were active both in
eliciting ACO expression and in the production of ethylene.
相似文献
36.
A change in twist of actin provides the force for the extension of the acrosomal process in limulus sperm: the false-discharge reaction 总被引:6,自引:5,他引:1
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One of the most spectacular motions is the generation of the acrosomal process in the limulus sperm. On contact with the egg, the sperm generates a 60-mum-long process that literally drills its way through the jelly surrounding the egg. This irresversible reaction takes only a few seconds. We suggested earlier that this motion is driven by a change in twist of the actin filaments comprising the acrosomal process. In this paper we analyze the so-called false discharge, a reversible reaction, in which the acrosomal filament bundle extends laterally from the base of the sperm and not anteriorly from the apex. Unlike the true discharge, which is straight, the false discharge is helical. Before extension, the filament bundle is coiled about the base of the sperm. In the coil, the bundle is not smoothly bent but consists of arms (straight segments) and elbows (corners) so that the coil looks like a 14-sided polygon. The extension of the false discharge works as follows: starting at the base of the bundle, the filaments change their twist which concomitantly changes the orientations of the elbows relative to each other; that is, in the coil, the elbows all like in a common plane, but after the change in twist, the plane of each elbow is rotated to be perpendicular to that of its neighbors. This change transforms the bundle from a compact coil into an extended left- handed helix. Because the basal end of the bundle is unconstrained, the extension is lateral. The true discharge works the same way but starts at the apical end of the bundle. The apical end, however, is constrained by its passage through the nuclear canal, which directs the extention anteriorly. Unlike the false discharge, during the true discharge the elbows are melted out, making the reaction irreversible. This study shows that rapid movement can be regenerated by actin without myosin and gives us insight into the molecular mechanism. 相似文献
37.
Hosfield DJ Zhang Y Dougan DR Broun A Tari LW Swanson RV Finn J 《The Journal of biological chemistry》2004,279(10):8526-8529
Farnesyl pyrophosphate synthetase (FPPS) synthesizes farnesyl pyrophosphate through successive condensations of isopentyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate. Nitrogen-containing bisphosphonate drugs used to treat osteoclast-mediated bone resorption and tumor-induced hypercalcemia are potent inhibitors of the enzyme. Here we present crystal structures of substrate and bisphosphonate complexes of FPPS. The structures reveal how enzyme conformational changes organize conserved active site residues to exploit metal-induced ionization and substrate positioning for catalysis. The structures further demonstrate how nitrogen-containing bisphosphonates mimic a carbocation intermediate to inhibit the enzyme. Together, these FPPS complexes provide a structural template for the design of novel inhibitors that may prove useful for the treatment of osteoporosis and other clinical indications including cancer. 相似文献
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