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381.
Sivaraman P Mattegunta S Subbaraju GV Satyanarayana C Padmanabhan B 《Systems and synthetic biology》2010,4(4):257-263
Sirtuins (class III histone deacetylase) are evolutionarily conserved NAD+-dependent enzymes that catalyze the deacetylation of acetyl-lysine residues of histones and other target proteins. Because
of their associations in various pathophysiological conditions, the identification of small molecule modulators has been of
significant interest. In the present study, virtual screening was carried out with NCI Diversity Set II using crystal structure
of hSIRT2 (PDB ID: 1J8F) as a model for the docking procedure to find potential compounds, which were then subjected to experimental
tests for their in vitro SIRT2 inhibitory activity. One of the 40 compounds tested, NSC671136 (IUPAC name: 6-Acetyl-4-oxo-1,3-diphenyl-2-thioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl
2,4-dichlorobenzoate) has structurally unique scaffold, showed strong inhibitory activity towards SIRT2 with IC50 of ~8.7 μM and to a lesser extent on SIRT1 activity. The reported compound is substantially potent compared to the published
SIRT2 inhibitors and serves as an excellent base for future lead development. 相似文献
382.
383.
Specific growth inhibitory sequences in genomic DNA from quiescent human embryo fibroblasts. 总被引:6,自引:1,他引:5
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We used HeLa cells as recipients in a gene transfer assay to characterize DNA sequences that negatively regulate mammalian cell growth. In this assay, genomic DNA from quiescent human embryo fibroblasts was more inhibitory for HeLa replication than was DNA from either Escherichia coli or HeLa cells. Surprisingly, growth inhibitory activity depended on the growth state of the cells from which genomic DNA was prepared; it was strongest in DNA prepared from serum-deprived, quiescent embryo fibroblasts. This latter observation implies a role for DNA modification(s) in regulating the activity of the inhibitory sequences detected in our assay. The level of the observed growth inhibitory activity was sometimes high, suggesting that the relevant sequences may be abundantly represented in the mammalian genome. We speculate that these findings may provide new insights into the molecular mechanisms involved in cellular quiescence and in vitro senescence. 相似文献
384.
Padmanabhan Bharanidharan 《International journal of biometeorology》1997,40(2):117-118
As part of an integrated geographical and environmental epidemiological study of multiple sclerosis (MS) in Budapest’s Pesterzsébet
district, many biometeorological variables were specifically examined. Also, the monthly distribution of birthdates of MS
patients resident in the district was plotted. Patients reliably diagnosed with MS were found to have been born in greater
numbers in the months of April and October, precisely 6 months apart. This finding indicates the presence of natural non-genetic
factors in the creation of MS susceptibility, affecting the nervous system at the crucial time of myelination.
Received: 25 March 1996 / Revised: 30 August 1996 / Accepted: 18 September 1996 相似文献
385.
386.
Processing and localization of Dengue virus type 2 polyprotein precursor NS3-NS4A-NS4B-NS5.
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Processing of dengue virus type 2 polyprotein precursor NS3-NS4A-NS4B-NS5 could be mediated by the catalytically active NS3 protease domain and NS2B in trans at the dibasic sites NS3-NS4A and NS4B-NS5. Subcellular localization of the unprocessed precursor NS3-NS4A-NS4B-NS5 showed that it was confined to a distinct subcellular organelle in the cytoplasm, which was distinct from the distribution of the mature NS5. 相似文献
387.
Purified plasma membrane vesicles isolated from multidrug-resistant human KB-V1 cells accumulate [3H]vinblastine in an energy-dependent manner. The accumulation of [3H]vinblastine in the presence of ATP is a saturable process. ATP can be replaced by other purine nucleotide triphosphates, of which GTP is the most efficient. 相似文献
388.
R Padmanabhan A G al-Zuhair 《Zeitschrift für mikroskopisch-anatomische Forschung》1990,104(2):212-230
Following induction of diabetes by a single injection of (IP) streptozotocin (STZ) to pregnant Wistar rats on days 2, 4 and 6 to 12 of gestation, fetuses and placentae were collected on day 20. The controls were either untreated or vehicle treated; alternatively following STZ injection, 2-6 IU of insulin was administered (sc) daily until term. The placentae were fixed in a glutaraldehyde and paraformaldehyde mixture and ultrathin sections were examined under the electron microscope. The structure of the vehicle treated control resembled that of the untreated control. The insulin control group had pathological changes similar to those of the diabetic group but with considerably less frequency. The giant cells in the basal zone of STZ group were numerous; they had abundant dilated cisternae of rough endoplasmic reticulum, intracytoplasmic fibrinoid and nuclear inclusions. The trophospongial cells presented numerous clear vacuoles, lysosomes and myelin bodies. Enlarged vacuoles often impinged deeply on the nucleus. The glycogen cells disintegrated resulting in cyst formation. In the labyrinthine zone, layer I trophoblast revealed increased number of large pores through which layer II trophoblast projected into the maternal sinusoid. Layer II had abundant glycogen, lipid droplets and lysosomes. Layer III had imbibed much fluid and appeared foamy with swollen organelles. Fibrinoid substance was produced by the giant cells, basophils and the trophoblast bordering the maternal sinusoids. Cyst development was preceded by degeneration of glycogen cells in the basal zone and of the trophoblast in the labyrinthine zone. Pronounced development of gonadotropin/somatotropin granule-like 'secretory granules' and smooth endoplasmic reticulum associated lipid droplets also characterised the labyrinthine trophoblast. The observed placental pathology appears to correlate well with the intrauterine growth retardation and fetal malformations recorded in this animal model. 相似文献
389.
A M de Vos M H Ultsch R F Kelley K Padmanabhan A Tulinsky M L Westbrook A A Kossiakoff 《Biochemistry》1992,31(1):270-279
The crystal structure of the kringle 2 domain of tissue plasminogen activator was determined and refined at a resolution of 2.43 A. The overall fold of the molecule is similar to that of prothrombin kringle 1 and plasminogen kringle 4; however, there are differences in the lysine binding pocket, and two looping regions, which include insertions in kringle 2, take on very different conformations. Based on a comparison of the overall structural homology between kringle 2 and kringle 4, a new sequence alignment for kringle domains is proposed that results in a division of kringle domains into two groups, consistent with their proposed evolutionary relation. The crystal structure shows a strong interaction between a lysine residue of one molecule and the lysine/fibrin binding pocket of a noncrystallographically related neighbor. This interaction represents a good model of a bound protein ligand and is the first such ligand that has been observed in a kringle binding pocket. The structure shows an intricate network of interactions both among the binding pocket residues and between binding pocket residues and the lysine ligand. A lysine side chain is identified as the positively charged group positioned to interact with the carboxylate of lysine and lysine analogue ligands. In addition, a chloride ion is located in the kringle-kringle interface and contributes to the observed interaction between kringle molecules. 相似文献
390.
The refined structure of the epsilon-aminocaproic acid complex of human plasminogen kringle 4. 总被引:1,自引:0,他引:1
The crystallographic structure of the plasminogen kringle 4-epsilon-aminocaproic acid (ACA) complex (K4-ACA) has been solved by molecular replacement rotation-translation methods utilizing the refined apo-K4 structure as a search model (Mulichak et al., 1991), and it has been refined to an R value of 0.148 at 2.25-A resolution. The K4-ACA structure consists of two interkringle residues, the kringle along with the ACA ligand, and 106 water molecules. The lysine-binding site has been confirmed to be a relatively open and shallow depression, lined by aromatic rings of Trp62, Phe64, and Trp72, which provide a highly nonpolar environment between doubly charged anionic and cationic centers formed by Asp55/Asp57 and Lys35/Arg71. A zwitterionic ACA ligand molecule is held by hydrogen-bonded ion pair interactions and van der Waals contacts between the charged centers. The lysine-binding site of apo-K4 and K4-ACA have been compared: the rms differences in main-chain and side-chain positions are 0.25 and 0.69 A, respectively, both practically within error of the determinations. The largest deviations in the binding site are due to different crystal packing interactions. Thus, the lysine-binding site appears to be preformed, and lysine binding does not require conformational changes of the host. The results of NMR studies of lysine binding with K4 are correlated with the structure of K4-ACA and agree well. 相似文献