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991.
Petr Stadlbauer Petra Kührová Pavel Baná? Jaroslav Ko?a Giovanni Bussi Luká? Trantírek Michal Otyepka Ji?í ?poner 《Nucleic acids research》2015,43(20):9626-9644
DNA G-hairpins are potential key structures participating in folding of human telomeric guanine quadruplexes (GQ). We examined their properties by standard MD simulations starting from the folded state and long T-REMD starting from the unfolded state, accumulating ∼130 μs of atomistic simulations. Antiparallel G-hairpins should spontaneously form in all stages of the folding to support lateral and diagonal loops, with sub-μs scale rearrangements between them. We found no clear predisposition for direct folding into specific GQ topologies with specific syn/anti patterns. Our key prediction stemming from the T-REMD is that an ideal unfolded ensemble of the full GQ sequence populates all 4096 syn/anti combinations of its four G-stretches. The simulations can propose idealized folding pathways but we explain that such few-state pathways may be misleading. In the context of the available experimental data, the simulations strongly suggest that the GQ folding could be best understood by the kinetic partitioning mechanism with a set of deep competing minima on the folding landscape, with only a small fraction of molecules directly folding to the native fold. The landscape should further include non-specific collapse processes where the molecules move via diffusion and consecutive random rare transitions, which could, e.g. structure the propeller loops. 相似文献
992.
Michal Brylinski 《PLoS computational biology》2014,10(9)
Detecting similarities between ligand binding sites in the absence of global homology between target proteins has been recognized as one of the critical components of modern drug discovery. Local binding site alignments can be constructed using sequence order-independent techniques, however, to achieve a high accuracy, many current algorithms for binding site comparison require high-quality experimental protein structures, preferably in the bound conformational state. This, in turn, complicates proteome scale applications, where only various quality structure models are available for the majority of gene products. To improve the state-of-the-art, we developed eMatchSite, a new method for constructing sequence order-independent alignments of ligand binding sites in protein models. Large-scale benchmarking calculations using adenine-binding pockets in crystal structures demonstrate that eMatchSite generates accurate alignments for almost three times more protein pairs than SOIPPA. More importantly, eMatchSite offers a high tolerance to structural distortions in ligand binding regions in protein models. For example, the percentage of correctly aligned pairs of adenine-binding sites in weakly homologous protein models is only 4–9% lower than those aligned using crystal structures. This represents a significant improvement over other algorithms, e.g. the performance of eMatchSite in recognizing similar binding sites is 6% and 13% higher than that of SiteEngine using high- and moderate-quality protein models, respectively. Constructing biologically correct alignments using predicted ligand binding sites in protein models opens up the possibility to investigate drug-protein interaction networks for complete proteomes with prospective systems-level applications in polypharmacology and rational drug repositioning. eMatchSite is freely available to the academic community as a web-server and a stand-alone software distribution at http://www.brylinski.org/ematchsite.
This is a PLOS Computational Biology Software Article相似文献
993.
Michal Hofer Milan Pospíšil Zuzana Hoferová Denisa Komůrková Petr Páral Filipp Savvulidi Luděk Šefc 《Purinergic signalling》2013,9(2):207-214
This study continues our earlier findings on the hematopoiesis-modulating effects of adenosine A1 and A3 receptor agonists that were performed on committed hematopoietic progenitor and precursor cell populations. In the earlier experiments, N 6-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, was found to inhibit proliferation in the above-mentioned hematopoietic cell systems, whereas N 6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA), an adenosine A3 receptor agonist, was found to stimulate it. The topic of this study was to evaluate the possibility that the above-mentioned adenosine receptor agonists modulate the behavior of early hematopoietic progenitor cells and hematopoietic stem cells. Flow cytometric analysis of hematopoietic stem cells in mice was employed, as well as a functional test of hematopoietic stem and progenitor cells (HSPCs). These techniques enabled us to study the effect of the agonists on both short-term repopulating ability and long-term repopulating ability, representing multipotent progenitors and hematopoietic stem cells, respectively. In a series of studies, we did not find any significant effect of adenosine agonists on HSPCs in terms of their numbers, proliferation, or functional activity. Thus, it can be concluded that CPA and IB-MECA do not significantly influence the primitive hematopoietic stem and progenitor cell pool and that the hematopoiesis-modulating action of these adenosine receptor agonists is restricted to more mature compartments of hematopoietic progenitor and precursor cells. 相似文献
994.
Michal Sobkowski Adam Kraszewski Jacek Stawiński 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):253-267
Abstract Three methods for the functionalization of oligonucleotides with aminoalkyl moieties have been developed and their efficiencies were evaluated in the preparation of non-radioactive hybridization probes. 相似文献
995.
Michal Sobkowski Jacek Stawinski Adam Kraszewski 《Nucleosides, nucleotides & nucleic acids》2013,32(8):628-645
Efficiency and stereoselectivity of condensations of ribonucleoside 3′-H-phosphonates with ethanol promoted by pivaloyl chloride were investigated as a function of tertiary amines used. Side reactions leading to an increased demand for the condensing agent were identified as derived from an attack of the pivalate anion at carbonyl centers of reactive pivaloyl derivatives. The conditions that secured quantitative yields of H-phosphonate diester condensations were assessed. Several tertiary amines promoted condensations with stereoselectivity higher than that observed for pyridine derivatives. A correlation between diastereoselectivity of the product formation and Brønsted and H-bonding basicities of the amine used was found. 相似文献
996.
997.
998.
Syam Prakash Somasekharan Michal Koc Alexandre Morizot Olivier Micheau Poul H. B. Sorensen Olivier Gaide Ladislav Andera Jean-Claude Martinou 《Apoptosis : an international journal on programmed cell death》2013,18(3):324-336
Recently, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) has been shown to be a potential candidate for cancer therapy. TRAIL induces apoptosis in various cancer cells but not in normal tissues. Here we show that HCT116 and SW480 cells with a deficient mitochondrial apoptotic pathway were resistant to TRAIL-induced apoptosis, whereas HCT116 and SW480 cells with a functional mitochondrial apoptotic pathway underwent apoptosis upon exposure to TRAIL. Surprisingly, TRAIL induced phenotypic changes in cells with a dysfunctional mitochondrial apoptotic pathway, including membrane blebbing and a transient loss of adhesion properties to the substratum. Accordingly, TRAIL stimulated the ability of these cells to migrate. This behavior was the consequence of a transient TRAIL-induced ROCK1 cleavage. In addition, we report that Bax-deficient HCT116 cells exposed to TRAIL for a prolonged period lost their sensitivity to TRAIL as a result of downregulation of TRAIL receptor expression, and became resistant to combination of TRAIL and other drugs such as MG-132 and bortezomib. These findings may have important consequences for TRAIL anti-cancer therapy. 相似文献
999.
Lenka Beranova Antonio R. Pombinho Jarmila Spegarova Michal Koc Magdalena Klanova Jan Molinsky Pavel Klener Petr Bartunek Ladislav Andera 《Apoptosis : an international journal on programmed cell death》2013,18(6):739-750
TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand from the TNF-alpha family that is under consideration, along with agonistic anti-TRAIL receptor antibodies, as a potential anti-tumor agent. However, most primary human tumors are resistant to monotherapy with TRAIL apoptogens, and thus the potential applicability of TRAIL in anti-tumor therapy ultimately depends on its rational combination with drugs targeting these resistances. In our high-throughput screening for novel agents/drugs that could sensitize TRAIL-resistant colorectal cancer cells to TRAIL-induced apoptosis, we found homoharringtonine (HHT), a cephalotaxus alkaloid and tested anti-leukemia drug, to be a very effective, low nanomolar enhancer of TRAIL-mediated apoptosis/growth suppression of these resistant cells. Co-treatment of TRAIL-resistant RKO or HT-29 cells with HHT and TRAIL led to the effective induction of apoptosis and the complete elimination of the treated cells. HHT suppressed the expression of the anti-apoptotic proteins Mcl-1 and cFLIP and enhanced the TRAIL-triggered activation of JNK and p38 kinases. The shRNA-mediated down-regulation of cFLIP or Mcl-1 in HT-29 or RKO cells variably enhanced their TRAIL-induced apoptosis but it did not markedly sensitize them to TRAIL-mediated growth suppression. However, with the notable exception of RKO/sh cFLIP cells, the downregulation of cFLIP or Mcl-1 significantly lowered the effective concentration of HHT in HHT + TRAIL co-treatment. Combined HHT + TRAIL therapy also led to the strong suppression of HT-29 tumors implanted into immunodeficient mice. Thus, HHT represents a very efficient enhancer of TRAIL-induced apoptosis with potential application in TRAIL-based, anti-cancer combination therapy. 相似文献
1000.
Jolanta Dorszewska Michal Prendecki Anna Oczkowska Agata Rozycka Margarita Lianeri Wojciech Kozubski 《Current Genomics》2013,14(8):518-533
Epinephrine (E) and sympathetic nerve stimulation were described
by Thomas Renton Elliott in 1905 for the
first time. Dopamine (DA), norepinephrine (NE), E, and serotonin
(5-HT) belong to the classic biogenic amines (or monoamines).
Parkinson’s disease (PD) is among the diseases in which it has
been established that catecholamines may account
for the neurodegeneration of central and peripheral
catecholamine neural systems. PD is a chronic and progressive
neurological disorder characterized by resting tremor, rigidity,
and bradykinesia, affecting 2% of individuals above the
age of 65 years. This disorder is a result of degeneration of
DA-producing neurons of the substantia nigra and a significant
loss of noradrenergic neurons in the locus coeruleus. In
PD and other related neurodegerative diseases, catecholamines
play the role of endogenous neurotoxins.
Catechol-O-methyltransferase (COMT) and/or monoamine oxidase
(MAO) catalyze the metabolism of monoamines. However, the
monoamine transporters for DA, NE, and 5-HT namely
DAT, NET, and SERT, respectively regulate the monoamine
concentration. The metabolism of catecholamines and 5-HT
involves common factors. Monoamine transporters represent
targets for many pharmacological agents that affect brain
function, including psychostimulators and antidepressants. In
PD, polymorphisms of the COMT, MAO, DAT, NET, and 5-
HTT genes may change the levels of biogenic amines and their
metabolic products. The currently available therapies for
PD improve the symptoms but do not halt the progression of the
disease. The most effective treatment for PD patients is
therapy with L-dopa. Combined therapy for PD involves a DA
agonist and decarboxylase, MAOs and COMT inhibitors,
and is the current optimal form of PD treatment maintaining monoamine
balance. 相似文献