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61.
62.
Zeynep Kurkcuoglu Ahmet Bakan Duygu Kocaman Ivet Bahar Pemra Doruker 《PLoS computational biology》2012,8(9)
Catalytic loop motions facilitate substrate recognition and binding in many enzymes. While these motions appear to be highly flexible, their functional significance suggests that structure-encoded preferences may play a role in selecting particular mechanisms of motions. We performed an extensive study on a set of enzymes to assess whether the collective/global dynamics, as predicted by elastic network models (ENMs), facilitates or even defines the local motions undergone by functional loops. Our dataset includes a total of 117 crystal structures for ten enzymes of different sizes and oligomerization states. Each enzyme contains a specific functional/catalytic loop (10–21 residues long) that closes over the active site during catalysis. Principal component analysis (PCA) of the available crystal structures (including apo and ligand-bound forms) for each enzyme revealed the dominant conformational changes taking place in these loops upon substrate binding. These experimentally observed loop reconfigurations are shown to be predominantly driven by energetically favored modes of motion intrinsically accessible to the enzyme in the absence of its substrate. The analysis suggests that robust global modes cooperatively defined by the overall enzyme architecture also entail local components that assist in suitable opening/closure of the catalytic loop over the active site. 相似文献
63.
The Application of CRISPR/Cas Technology to Efficiently Model Complex Cancer Genomes in Stem Cells
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Adam Albitar Bahar Rohani Brett Will Annie Yan G. Ian Gallicano 《Journal of cellular biochemistry》2018,119(1):134-140
CRISPR/Cas gene editing technologies have emerged as powerful tools in the study of oncogenic transformation. The system's specificity, versatility, and ease of implementation allow researchers to identify important molecular markers and pathways which grant cancers stem cell like properties. This technology has already been applied to researching specific cancers, but has seen restricted therapeutic applications due to inherent ethical and technical limitations. Active development and adaptation of the CRISPR/Cas system has produced new methods to take advantage of both non‐homologous end joining and homologous recombination repair mechanisms in attempts to remedy these limitations and improve the versatility of gene edits that can be created. Nonetheless, until issues with specificity and in vivo efficiency are resolved, utilization of CRISPR/Cas systems would be best employed in the modeling and study of various cancer genes. While it may have potential therapeutic applications to targeted cancer therapies in the future, presently CRISPR/Cas is a remarkable technique that can be utilized for easy and efficient gene editing when it comes to cancer research. J. Cell. Biochem. 119: 134–140, 2018. © 2017 Wiley Periodicals, Inc. 相似文献
64.
Penetration into membrane of amino‐terminal region of SecA when associated with SecYEG in active complexes
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Bahar T. Findik Virginia F. Smith Linda L. Randall 《Protein science : a publication of the Protein Society》2018,27(3):681-691
The general secretory (Sec) system of Escherichia coli translocates both periplasmic and outer membrane proteins through the cytoplasmic membrane. The pathway through the membrane is provided by a highly conserved translocon, which in E. coli comprises two heterotrimeric integral membrane complexes, SecY, SecE, and SecG (SecYEG), and SecD, SecF, and YajC (SecDF/YajC). SecA is an associated ATPase that is essential to the function of the Sec system. SecA plays two roles, it targets precursors to the translocon with the help of SecB and it provides energy via hydrolysis of ATP. SecA exists both free in the cytoplasm and integrally membrane associated. Here we describe details of association of the amino‐terminal region of SecA with membrane. We use site‐directed spin labelling and electron paramagnetic resonance spectroscopy to show that when SecA is co‐assembled into lipids with SecYEG to yield highly active translocons, the N‐terminal region of SecA penetrates the membrane and lies at the interface between the polar and the hydrophobic regions, parallel to the plane of the membrane at a depth of approximately 5 Å. When SecA is bound to SecYEG, preassembled into proteoliposomes, or nonspecifically bound to lipids in the absence of SecYEG, the N‐terminal region penetrates more deeply (8 Å). Implications of partitioning of the SecA N‐terminal region into lipids on the complex between SecB carrying a precursor and SecA are discussed. 相似文献
65.
Role of water on unfolding kinetics of helical peptides studied by molecular dynamics simulations
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Molecular dynamics simulations have been carried out with four polypeptides, Ala13, Val(13), Ser13, and Ala4Gly5Ala4, in vacuo and with explicit hydration. The unfolding of the polypeptides, which are initially fully alpha-helix in conformation, has been monitored during trajectories of 0.3 ns at 350 K. A rank of Ala < Val < Ser < Gly is found in the order of increasing rate of unwinding. The unfolding of Ala13 and Val(13) is completed in hundreds of picoseconds, while that of Ser13 is about one order of magnitude faster. The helix content of the peptide containing glycine residues falls to zero within a few picoseconds. Ramachandran plots indicate quite distinct equilibrium distributions and time evolution of dihedral angles in water and in vacuum for each residue type. The unfolding of polyalanine and polyvaline helices is accelerated due to solvation. In contrast, polyserine is more stable in water compared to vacuum, because its side chains can form intramolecular hydrogen bonds with the backbone more readily in vacuum, which disrupts the helix. Distribution functions of the spatial and angular position of water molecules in the proximity of the polypeptide backbone polar groups reveal the stabilization of the coiled structures by hydration. The transition from helix to coil is characterized by the appearance of a new peak in the probability distribution at a specific location characteristic of hydrogen bond formation between water and backbone polar groups. No significant insertion of water molecules is observed at the precise onset of unwinding, while (i, i+3) hydrogen bond formation is frequently detected at the initiation of alpha-helix unwinding. 相似文献
66.
RNA bulge entropies in the unbound state correlate with peptide binding strengths for HIV-1 and BIV TAR RNA because of improved conformational access.
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For the binding of peptides to wild-type HIV-1 and BIV TAR RNA and to mutants with bulges of various sizes, changes in the DeltaDelta G values of binding were determined from experimental K d values. The corresponding entropies of these bulges are estimated by enumerating all possible RNA bulge conformations on a lattice and then applying the Boltzmann relationship. Independent calculations of entropies from fluctuations are also carried out using the Gaussian network model (GNM) recently introduced for analyzing folded structures. Strong correlations are seen between the changes in free energy determined for binding and the two different unbound entropy calculations. The fact that the calculated entropy increase with larger bulge size is correlated with the enhanced experimental binding free energy is unusual. This system exhibits a dependence on the entropy of the unbound form that is opposite to usual binding models. Instead of a large initial entropy being unfavorable since it would be reduced upon binding, here the larger entropies actually favor binding. Several interpretations are possible: (i) the higher conformational freedom implies a higher competence for binding with a minimal strain, by suitable selection amongst the set of already accessible conformations; (ii) larger bulge entropies enhance the probability of the specific favorable conformation of the bound state; (iii) the increased freedom of the larger bulges contri-butes more to the bound state than to the unbound state; (iv) indirectly the large entropy of the bound state might have an unfavorable effect on the solvent structure. Nonetheless, this unusual effect is interesting. 相似文献
67.
Targeted Disruption of CDK4 Delays Cell Cycle Entry with Enhanced p27Kip1 Activity 总被引:16,自引:0,他引:16
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Tateki Tsutsui Bahar Hesabi David S. Moons Pier Paolo Pandolfi Kimberly S. Hansel Andrew Koff Hiroaki Kiyokawa 《Molecular and cellular biology》1999,19(10):7011-7019
The mechanism by which cyclin-dependent kinase 4 (CDK4) regulates cell cycle progression is not entirely clear. Cyclin D/CDK4 appears to initiate phosphorylation of retinoblastoma protein (Rb) leading to inactivation of the S-phase-inhibitory action of Rb. However, cyclin D/CDK4 has been postulated to act in a noncatalytic manner to regulate the cyclin E/CDK2-inhibitory activity of p27(Kip1) by sequestration. In this study we investigated the roles of CDK4 in cell cycle regulation by targeted disruption of the mouse CDK4 gene. CDK4(-/-) mice survived embryogenesis and showed growth retardation and reproductive dysfunction associated with hypoplastic seminiferous tubules in the testis and perturbed corpus luteum formation in the ovary. These phenotypes appear to be opposite to those of p27-deficient mice such as gigantism and gonadal hyperplasia. A majority of CDK4(-/-) mice developed diabetes mellitus by 6 weeks, associated with degeneration of pancreatic islets. Fibroblasts from CDK4(-/-) mouse embryos proliferated similarly to wild-type embryonic fibroblasts under conditions that promote continuous growth. However, quiescent CDK4(-/-) fibroblasts exhibited a substantial ( approximately 6-h) delay in S-phase entry after serum stimulation. This cell cycle perturbation by CDK4 disruption was associated with increased binding of p27 to cyclin E/CDK2 and diminished activation of CDK2 accompanied by impaired Rb phosphorylation. Importantly, fibroblasts from CDK4(-/-) p27(-/-) embryos displayed partially restored kinetics of the G(0)-S transition, indicating the significance of the sequestration of p27 by CDK4. These results suggest that at least part of CDK4's participation in the rate-limiting mechanism for the G(0)-S transition consists of controlling p27 activity. 相似文献
68.
Persistent bacterial infections do not respond to current antibiotic treatments and thus present a great medical challenge. These conditions have been linked to the formation of dormant subpopulations of bacteria, known as persister cells, that are growth-arrested and highly tolerant to conventional antibiotics. Here, we report a new strategy of persister control and demonstrate that minocycline, an amphiphilic antibiotic that does not require active transport to penetrate bacterial membranes, is effective in killing Escherichia coli persister cells [by 70.8 ± 5.9% (0.53 log) at 100 μg/mL], while being ineffective in killing normal cells. Further mechanistic studies revealed that persister cells have reduced drug efflux and accumulate more minocycline than normal cells, leading to effective killing of this dormant subpopulation upon wake-up. Consistently, eravacycline, which also targets the ribosome but has a stronger binding affinity than minocycline, kills persister cells by 3 logs when treated at 100 μg/mL. In summary, the findings of this study reveal that while dormancy is a well-known cause of antibiotic tolerance, it also provides an Achilles’ heel for controlling persister cells by leveraging dormancy associated reduction of drug efflux. 相似文献
69.
Mahbub Khandaker Rayhan Bahar Md Mezbaul Labbate Maurizio Krishnan Kannan Andrews Stuart Naidu Ravi Megharaj Mallavarapu 《Applied microbiology and biotechnology》2017,101(3):963-976
Applied Microbiology and Biotechnology - Contamination of land and water caused by heavy metal mercury (Hg) poses a serious threat to biota worldwide. The seriousness of toxicity of this neurotoxin... 相似文献
70.
Relationship between river water quality and land use in a small river basin running through the urbanizing area of Central Japan 总被引:9,自引:0,他引:9
In this study, the relationship between water quality (as represented by major inorganic ion concentrations) and land use
characteristics is examined for a small river basin which runs through the urbanizing area of central Japan. Water samples
were taken from 24 sites at base flow and analyzed, and the proportions of the various land uses associated with the respective
drainage basins were calculated using a digital land-use map (scale: 1:25000). The electrical conductivity (EC) of the water
ranged from 84.5 to 600 μS cm−1. Ca2+ and Na+ were the major cations, accounting for 77% of all cations. Among the anions, HCO3
− was dominant (56%), followed by Cl− (24%), SO4
2− (13%) and NO3
− (7%). Applying principal component analysis to land use in the drainage basin yielded three principal components. The first
principal component expressed the degree of occupation by residential areas, the second indicated the degree of urban developing
area (i.e., fast-developing and industrial areas), and the third showed the degree of coverage with farmland and green space.
The residential area showed significant positive correlations with K+, Mg2+, Ca2+, NO3
−, HCO3
−, EC and TMI (total major ions). Urban developing area showed significant positive correlations with Ca2+, Cl−, HCO3
−, EC and TMI as well as weak negative correlations with NO3
− and SO4
2−. Industrial area showed weak positive correlations with Na+ and Cl− and a moderate negative correlation with NO3
−. Farmland showed significant positive correlations with NO3
− and SO4
2−; these ions are present due to fertilizers and the biological activity of plants. Forest area is inversely related to almost
all ions, indicating the need for this form of land use in order to maintain river water quality. 相似文献