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31.
Nithya BabuRajendran Paaventhan Palasingam Kamesh Narasimhan Wenjie Sun Shyam Prabhakar Ralf Jauch Prasanna R. Kolatkar 《Nucleic acids research》2010,38(10):3477-3488
Smad1 is a downstream effector of the BMP signaling pathway that binds regulatory DNA to execute gene expression programs leading to, for example, the maintenance of pluripotency in mice. On the contrary, the TGF-β-activated Smad3 triggers strikingly different programs such as mesodermal differentiation in early development. Because Smad1 and Smad3 contain identical amino acids at the DNA contact interface it is unclear how they elicit distinctive bioactivities. Here, we report the crystal structure of the MH1 domain of Smad1 bound to a palindromic Smad binding element. Surprisingly, the DNA contact interface of Smad1 is drastically rearranged when compared to Smad3. The N-terminal helix 1 of Smad1 is dislodged from its intramolecular binding site and adopts a domain swapped arrangement with a symmetry-related molecule. As a consequence, helix 2 kinks away from the double helix disabling several key phosphate backbone interactions. Thermal melting analysis corroborates a decompacted conformation of Smad1 and DNA binding assays indicate a lower overall affinity of Smad1 to DNA but increased cooperativity when binding to palindromic DNA motifs. These findings suggest that Smad1 and Smad3 evolved differential qualities to assemble on composite DNA elements and to engage in co-factor interactions by remodeling their N-termini. 相似文献
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33.
Sindhuja Sundaram Prabhakar Tiwari Shalini Saini Rajiv Kant Joseph Alex Davis Sudhir Sahdev Kulvinder Singh Saini 《Molecular Biology》2010,44(3):473-478
Protein tyrosine phosphatases (PTPs) play multiple roles in many physiological processes. Over-expression of the PTPs has been shown to be associated with cellular toxicity, which may also lead to the deletion of the respective gene from stable cell clones. We also observed that PTP-1B over-expression in CHO and HEK293 stable cell clones led to cytotoxicity and low revival rates during clone generation and maintenance. To address these issues, bacmid transposition technology was utilized to generate recombinant PTP-1B baculovirus, and Spodoptera frugiperda (Sf9 and Sf21) insect cell lines were infected with the virus. The data obtained on expression and activity of the PTP-1B highlights clear advantage of the recombinant baculovi-rus-insect cell expression system over the mammalian cell line technique due to increase in enzyme activity, strongly inhibited by phosphatase specific inhibitor RK682. Possible application of the expression system for producing active enzymes in bulk quantity for a new drug discovery is also discussed. 相似文献
34.
Shannon F Stewman Matthew Jones-Rhoades Prabhakar Bhimalapuram Martin Tchernookov Daphne Preuss Aaron R Dinner 《BMC plant biology》2010,10(1):32
Background
Plant biologists have long speculated about the mechanisms that guide pollen tubes to ovules. Although there is now evidence that ovules emit a diffusible attractant, little is known about how this attractant mediates interactions between the pollen tube and the ovules. 相似文献35.
The functional sites were predicted for Nudix enzymes from pathogenic microorganisms such as Streprococcus pneumonia (2B06) and Enterococcus faecalis (2AZW). Their structures are already determined, however, no data is reported about their functional sites, substrates and inhibitors. Therefore, we report prediction of functional sites in these Nudix enzymes via Geometric Invariant (GI) technique (Construct different geometries of peptides which remain unchanged). The GI method enumerated 2B06: RA57, EA58, EA61, EA62 and 2AZW: RA62, EA63, EA66, EA67 as putative functional sites in these Nudix enzymes. In addition, the substrate was predicted via Molecular docking (Docking of substrates against whole structure of Nudix enzymes). The substrate ADP-Ribose was docked with the Nudix enzymes, 2B06 (Docking energy -15.68 Kcal/mol) and 2AZW (Docking energy -10.86 Kcal/mol) with the higher affinity and the lower docking energy as compared to other substrates. The residues EA62 in 2B06 and RA62 in 2AZW make hydrogen bonds with the ADP-ribose. Furthermore, we screened 51 inhibitor compounds against structures of 2B06 and 2AZW. The inhibitor compounds AMPCPR and CID14258187 were docked well as compared to other compounds. The compound CID14258187 was also in agreement with Lipinski rule of 5 for drug likeness properties. Therefore, our findings of functional sites, substrates and inhibitors for these Nudix enzymes may help in structure based drug designing against Streprococcus pneumonia and Enterococcus faecalis. 相似文献
36.
Fine Mapping QTL for Drought Resistance Traits in Rice (<Emphasis Type="Italic">Oryza sativa</Emphasis> L.) Using Bulk Segregant Analysis 总被引:1,自引:0,他引:1
Salunkhe AS Poornima R Prince KS Kanagaraj P Sheeba JA Amudha K Suji KK Senthil A Babu RC 《Molecular biotechnology》2011,49(1):90-95
Drought stress is a major limitation to rice (Oryza sativa L.) yields and its stability, especially in rainfed conditions. Developing rice cultivars with inherent capacity to withstand
drought stress would improve rainfed rice production. Mapping quantitative trait loci (QTLs) linked to drought resistance
traits will help to develop rice cultivars suitable for water-limited environments through molecular marker-assisted selection
(MAS) strategy. However, QTL mapping is usually carried out by genotyping large number of progenies, which is labour-intensive,
time-consuming and cost-ineffective. Bulk segregant analysis (BSA) serves as an affordable strategy for mapping large effect
QTLs by genotyping only the extreme phenotypes instead of the entire mapping population. We have previously mapped a QTL linked
to leaf rolling and leaf drying in recombinant inbred (RI) lines derived from two locally adapted indica rice ecotypes viz., IR20/Nootripathu using BSA. Fine mapping the QTL will facilitate its application in MAS. BSA was done
by bulking DNA of 10 drought-resistant and 12 drought-sensitive RI lines. Out of 343 rice microsatellites markers genotyped,
RM8085 co-segregated among the RI lines constituting the respective bulks. RM8085 was mapped in the middle of the QTL region
on chromosome 1 previously identified in these RI lines thus reducing the QTL interval from 7.9 to 3.8 cM. Further, the study
showed that the region, RM212–RM302–RM8085–RM3825 on chromosome 1, harbours large effect QTLs for drought-resistance traits
across several genetic backgrounds in rice. Thus, the QTL may be useful for drought resistance improvement in rice through
MAS and map-based cloning. 相似文献
37.
Earlier, we have shown that GM-CSF-exposed CD8α- DCs that express low levels of pro-inflammatory cytokines IL-12 and IL-1β can induce Foxp3+ Tregs leading to suppression of autoimmunity. Here, we examined the differential effects of IL-12 and IL-1β on Foxp3 expression in T cells when activated in the presence and absence of DCs. Exogenous IL-12 abolished, but IL-1β enhanced, the ability of GM-CSF-exposed tolerogenic DCs to promote Foxp3 expression. Pre-exposure of DCs to IL-1β and IL-12 had only a modest effect on Foxp3- expressing T cells; however, T cells activated in the absence of DCs but in the presence of IL-1β or IL-12 showed highly significant increase and decrease in Foxp3+ T cell frequencies respectively suggesting direct effects of these cytokines on T cells and a role for IL-1β in promoting Foxp3 expression. Importantly, purified CD4+CD25+ cells showed a significantly higher ability to maintain Foxp3 expression when activated in the presence of IL-1β. Further analyses showed that the ability of IL-1β to maintain Foxp3 expression in CD25+ T cells was dependent on TGF-β1 and IL-2 expression in Foxp3+Tregs and CD25- effectors T cells respectively. Exposure of CD4+CD25+ T cells to IL-1β enhanced their ability to suppress effector T cell response in vitro and ongoing experimental autoimmune thyroidits in vivo. These results show that IL-1β can help enhance/maintain Tregs, which may play an important role in maintaining peripheral tolerance during inflammation to prevent and/or suppress autoimmunity. 相似文献
38.
A series of 4-thiazolidinones were evaluated as selective inhibitors of the HIV-RT enzyme. Our attempt in correlating the derived physicochemical properties with the HIV-RT inhibitory activity resulted in some statistically significant QSAR models with good predictive ability. The QSAR studies indicated the role of lipophilicity, dipole moment and out-of-plane potential energy of the compounds in rationalizing the activity. One of the compounds, 1, inhibited the enzyme at 0.204 μM concentration with minimal toxicity to MT-4 cells. 相似文献
39.
Qiao JX Cheng X Modi DP Rossi KA Luettgen JM Knabb RM Jadhav PK Wexler RR 《Bioorganic & medicinal chemistry letters》2005,15(1):29-35
Syntheses and SAR studies of 5-amidinobenzo[b]thiophene analogs provided compounds with low submicromolar factor IXa activity and equal or slightly better selectivity relative to factor Xa. 相似文献
40.