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131.
Adwait Anand Godbole Wareed Ahmed Rajeshwari Subray Bhat Erin K. Bradley Sean Ekins Valakunja Nagaraja 《Biochemical and biophysical research communications》2014
m-AMSA, an established inhibitor of eukaryotic type II topoisomerases, exerts its cidal effect by binding to the enzyme–DNA complex thus inhibiting the DNA religation step. The molecule and its analogues have been successfully used as chemotherapeutic agents against different forms of cancer. After virtual screening using a homology model of the Mycobacterium tuberculosis topoisomerase I, we identified m-AMSA as a high scoring hit. We demonstrate that m-AMSA can inhibit the DNA relaxation activity of topoisomerase I from M. tuberculosis and Mycobacterium smegmatis. In a whole cell assay, m-AMSA inhibited the growth of both the mycobacteria. 相似文献
132.
Molecular determinants of the binding specificity of BH3 ligands to BclXL apoptotic repressor
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Vikas Bhat Max B. Olenick Brett J. Schuchardt David C. Mikles Caleb B. McDonald Amjad Farooq 《Biopolymers》2014,101(6):573-582
B‐cell lymphoma extra‐large protein (BclXL) serves as an apoptotic repressor by virtue of its ability to recognize and bind to BH3 domains found within a diverse array of proapoptotic regulators. Herein, we investigate the molecular basis of the specificity of the binding of proapoptotic BH3 ligands to BclXL. Our data reveal that while the BH3 ligands harboring the LXXX[A/S]D and [R/Q]XLXXXGD motif bind to BclXL with high affinity in the submicromolar range, those with the LXXXGD motif afford weak interactions. This suggests that the presence of a glycine at the fourth position (G+4)—relative to the N‐terminal leucine (L0) within the LXXXGD motif—mitigates binding, unless the LXXXGD motif also contains arginine/glutamine at the ?2 position. Of particular note is the observation that the residues at the +4 and ?2 positions within the LXXX[A/S]D and [R/Q]XLXXXGD motifs appear to be energetically coupled—replacement of either [A/S]+4 or [R/Q]‐2 with other residues has little bearing on the binding affinity of BH3 ligands harboring one of these motifs. Collectively, our study lends new molecular insights into understanding the binding specificity of BH3 ligands to BclXL with important consequences on the design of novel anticancer drugs. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 573–582, 2014. 相似文献
133.
Insulin-stimulated translocation of glucose transporter 4 (GLUT4) to cell membrane leading to glucose uptake is the rate-limiting
step in diabetes. It is also a defined target of antidiabetic drug research. Existing GLUT4 translocation assays are based
on time-consuming immunoassays and are hampered by assay variability and low sensitivity. We describe a real-time, visual,
cell-based qualitative GLUT4 translocation assay using CHO-HIRc-myc-GLUT4eGFP cells that stably express myc- and eGFP-tagged
GLUT4 in addition to human insulin receptor (HIRc). GLUT4 translocation is visualized by live cell imaging based on GFP fluorescence
by employing a cooled charge-coupled device camera attached to a fluorescent microscope. This video imaging method and further
quantitative analysis of GLUT4 on the cell membrane provide rapid and foolproof visual evidence that this method is suitable
for screening GLUT4 translocation modulators. 相似文献
134.
S. Siju K. Dhanya S. Syamkumar T.E. Sheeja B. Sasikumar A.I. Bhat V.A. Parthasarathy 《Biochemical Systematics and Ecology》2010
Development of a robust set of 18 genomic microsatellite markers from turmeric (Curcuma longa L.) and its effective utilization in estimating the genetic diversity of 20 turmeric accessions are described. A total of 103 alleles were detected with an average of 5.7 alleles per locus. These markers displayed varied levels of polymorphism as evident from its discriminating power ranging from 0.19 to 0.70. The UPGMA cluster analysis of genetic distance values resolved the 20 turmeric accessions into five main groups. Three sets of genetically identical accessions were detected within the analyzed accessions, suggesting a revisit of the germplasm collection strategy based on vernacular identity. The entire grouping pattern of the entities was loose and independent of their geographical origins. These polymorphic SSR markers would be useful for the population genetic studies and germplasm management of turmeric. 相似文献
135.
Steven T. Staben Timothy P. Heffron Daniel P. Sutherlin Seema R. Bhat Georgette M. Castanedo Irina S. Chuckowree Jenna Dotson Adrian J. Folkes Lori S. Friedman Leslie Lee John Lesnick Cristina Lewis Jeremy M. Murray Jim Nonomiya Alan G. Olivero Emile Plise Jodie Pang Wei Wei Prior Laurent Salphati Lionel Rouge Bing-Yan Zhu 《Bioorganic & medicinal chemistry letters》2010,20(20):6048-6051
Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model. 相似文献
136.
Wild type p53 exists in a constant state of equilibrium between wild type and mutant conformation and undergoes conformational changes at elevated temperature. We have demonstrated that the co-chaperone CHIP (carboxyl terminus of Hsp70-interacting protein), which suppressed aggregation of several misfolded substrates and induced the proteasomal degradation of both wild type and mutant p53, physically interacts with the amino terminus of WT53 and prevented it from irreversible thermal inactivation. CHIP preferentially binds to the p53 mutant phenotype and restored the DNA binding activity of heat-denatured p53 in an ATP-independent manner. In cells under elevated temperatures that contained a higher level of p53 mutant phenotype, CHIP restored the native-like conformation of p53 in the presence of geldanamycin, whereas CHIP-small interfering RNA considerably increased the mutant form. Further, under elevated temperatures, the levels of CHIP and p53 were higher in nucleus, and chromatin immunoprecipitation shows the presence of p53 and CHIP together upon the DNA binding site in the p21 and p53 promoters. We propose that CHIP might be a direct chaperone of wild type p53 that helps p53 in maintaining wild type conformation under physiological condition as well as help resurrect p53 mutant phenotype into a folded native state under stress condition. 相似文献
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139.
The role of mitochondria in causing diseases is becoming evident as more and more studies are focusing on this organelle of
the cell. This is largely attributed to its reactive oxygen species (ROS) production property. In the context of diabetes,
ROS is suggested to trigger different forms of insulin resistance involving different mechanisms. The suggestive role of a
mtDNA variant G10398A in increasing ROS production and the impaired response to oxidative stress due to T16189C variant is
worth addressing as genetic susceptibility factors in type 2 diabetes mellitus (T2DM). A case control study on 312 T2DM cases
and ethnically matched 466 controls involving two North Indian populations, referred as cohort 1 and cohort 2 (in a replicative
study), was undertaken to test such a genetic association. A statistically significant association was observed for 10398A
allele in both the cohorts [cohort1 (OR = 2.67 95% CI 1.77–4.00); cohort2 (OR = 1.76 95%CI 1.12–2.77)]. The analysis of G10398A/T16189C
haplotypic combinations revealed that 10398A/16189C haplotype provides a risk in both the cohorts. To sum up the study suggests
that 10398A and 16189C alleles provide susceptiblity to T2DM independently as well as together. 相似文献
140.
Gholap AR Toti KS Shirazi F Kumari R Bhat MK Deshpande MV Srinivasan KV 《Bioorganic & medicinal chemistry》2007,15(21):6705-6715
A series of 2-amino-5-oxo-4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile and various analogues have been synthesized in excellent isolated yields starting from various arylidenemalononitrile and 3-amino-2-cyclohexen-1-one in 1-propanol as solvent at reflux temperature in the absence of any added catalyst. All the synthesized compounds were evaluated for their antifungal activity. The relationship between functional group variation and biological activity of the evaluated compounds is discussed in the article. 相似文献