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131.
A Siarheyeva G Senisterra A Allali-Hassani A Dong E Dobrovetsky GA Wasney I Chau R Marcellus T Hajian F Liu I Korboukh D Smil Y Bolshan J Min H Wu H Zeng P Loppnau G Poda C Griffin A Aman PJ Brown J Jin R Al-Awar CH Arrowsmith M Schapira M Vedadi 《Structure (London, England : 1993)》2012,20(8):1425-1435
PRMT3, a protein arginine methyltransferase, has been shown to influence ribosomal biosynthesis by catalyzing the dimethylation of the 40S ribosomal protein S2. Although PRMT3 has been reported to be a cytosolic protein, it has been shown to methylate histone H4 peptide (H4 1-24) in?vitro. Here, we?report the identification of a PRMT3 inhibitor (1-(benzo[d][1,2,3]thiadiazol-6-yl)-3-(2-cyclohexenylethyl)urea; compound 1) with IC(50) value of 2.5?μM by screening a library of 16,000 compounds using H4 (1-24) peptide as a substrate. The crystal structure of PRMT3 in complex with compound 1 as well as kinetic analysis reveals an allosteric mechanism of inhibition. Mutating PRMT3 residues within the allosteric site or using compound 1 analogs that disrupt interactions with allosteric site residues both abrogated binding and inhibitory activity. These data demonstrate an allosteric mechanism for inhibition of protein arginine methyltransferases, an emerging class of therapeutic targets. 相似文献
132.
La Carbona S Sauvageot N Giard JC Benachour A Posteraro B Auffray Y Sanguinetti M Hartke A 《Molecular microbiology》2007,66(5):1148-1163
The opportunistic pathogen Enterococcus faecalis is well equipped with peroxidatic activities. It harbours three loci encoding a NADH peroxidase, an alkyl hydroperoxide reductase and a protein (EF2932) belonging to the AhpC/TSA family. We present results demonstrating that ef2932 does encode a thiol peroxidase (Tpx) and show that it is part of the regulon of the hydrogen peroxide regulator HypR. Characterization of unmarked deletion mutants showed that all three peroxidases are important for the defence against externally provided H(2)O(2). Exposure to internal generated H(2)O(2) by aerobic growth on glycerol, lactose, galactose or ribose showed that Npr was absolutely required for aerobic growth on glycerol and optimal growth on the other substrates. Growth on glycerol was also dependent on Ahp. Addition of catalase restored growth of the mutants, and therefore, extracellular H(2)O(2) concentrations have been determined. This showed that the time point of growth arrest of the Deltanpr mutant correlated with the highest H(2)O(2) concentration measured. Analysis of the survival of the different strains inside peritoneal macrophages revealed that Tpx was the most important antioxidant activity for protecting the cells against the hostile phagocyte environment. Finally, the Deltatpx and the triple mutant showed attenuated virulence in a mouse peritonitis model. 相似文献
133.
Plasmids play a central role in engineering recombinant bacteria because they are the primary vehicles used to manipulate
targeted sequences. In some cases, bacteria of interest are poorly provided with suitable tools for these molecular or genetic
manipulations. In this context, we constructed from two shuttle cloning vectors, pUCB2871 and pUCB2872, the basic vectors
pUCB30 and pUCB31, which could represent suitable tools to isolate replicons from Gram-positive bacteria. These plasmid vectors
are characterized by the following after-features: (a) the pUC origin of replication is unable to replicate in Gram-positive
bacteria; (b) an erythromycin-resistance encoding gene that is functional in both Gram-negative and -positive bacteria; (c)
the pUC19 multiple cloning site (MCS) within the lacZα reporter gene; and (4) an additional multiple cloning site (MCS). Cloning replicons from Gram-positive bacteria in this
additional MCS would allow the derivative vectors to function directly as shuttle cloning vectors. 相似文献
134.
David McGowan Origène Nyanguile Maxwell D. Cummings Sandrine Vendeville Koen Vandyck Walter Van den Broeck Carlo W. Boutton Hendrik De Bondt Ludo Quirynen Katie Amssoms Jean-François Bonfanti Stefaan Last Klara Rombauts Abdellah Tahri Lili Hu Frédéric Delouvroy Katrien Vermeiren Geneviève Vandercruyssen Liesbet Van der Helm Erna Cleiren Pierre Raboisson 《Bioorganic & medicinal chemistry letters》2009,19(9):2492-2496
Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC50 = 400 nM and 270 nM, respectively) and selective (CC50 > 20 μM) inhibitors of HCV replication. These data warrant further lead-optimization efforts. 相似文献
135.
Nady N Lemak A Walker JR Avvakumov GV Kareta MS Achour M Xue S Duan S Allali-Hassani A Zuo X Wang YX Bronner C Chédin F Arrowsmith CH Dhe-Paganon S 《The Journal of biological chemistry》2011,286(27):24300-24311
Histone modifications and DNA methylation represent two layers of heritable epigenetic information that regulate eukaryotic chromatin structure and gene activity. UHRF1 is a unique factor that bridges these two layers; it is required for maintenance DNA methylation at hemimethylated CpG sites, which are specifically recognized through its SRA domain and also interacts with histone H3 trimethylated on lysine 9 (H3K9me3) in an unspecified manner. Here we show that UHRF1 contains a tandem Tudor domain (TTD) that recognizes H3 tail peptides with the heterochromatin-associated modification state of trimethylated lysine 9 and unmodified lysine 4 (H3K4me0/K9me3). Solution NMR and crystallographic data reveal the TTD simultaneously recognizes H3K9me3 through a conserved aromatic cage in the first Tudor subdomain and unmodified H3K4 within a groove between the tandem subdomains. The subdomains undergo a conformational adjustment upon peptide binding, distinct from previously reported mechanisms for dual histone mark recognition. Mutant UHRF1 protein deficient for H3K4me0/K9me3 binding shows altered localization to heterochromatic chromocenters and fails to reduce expression of a target gene, p16(INK4A), when overexpressed. Our results demonstrate a novel recognition mechanism for the combinatorial readout of histone modification states associated with gene silencing and add to the growing evidence for coordination of, and cross-talk between, the modification states of H3K4 and H3K9 in regulation of gene expression. 相似文献
136.
S. Flahaut Abdellah Benachour Jean-Christophe Giard Philippe Boutibonnes Yanick Auffray 《Archives of microbiology》1996,165(5):317-324
Enterococcus faecalis was strongly resistant to high osmotic pressure in complex medium; however, when it was subjected to a moderate osmotic stress
[6.5% (w/v) NaCl or 52% (w/v) sucrose] for 2 h, it showed cross-protection against ethanol (22%), detergents stresses [bile
salts (0.3%) and SDS (0.017%)], hydrogen peroxide challenge (45 mM), and to a minor extent against lethal temperature (62° C).
In response to salt stress [6.5% (w/v) NaCl], E. faecalis induced a large number of stress proteins. In addition, NaCl strongly induced the synthesis of many proteins more than tenfold.
Although the acquired thermotolerance was inhibited markedly by chloramphenicol, the other NaCl-induced cross-tolerances seemed
not to be correlated with de novo protein synthesis. The relationship between the stress protein synthesis and the induction
of different types of cross-protection is discussed.
Received: 7 September 1995 / Accepted: 29 January 1996 相似文献
137.
A detailed study of the upper Pleistocene and Holocene ostracode fauna from the Moroccan margin of the Western Mediterranean is here presented based on sediments of three cores drilled near the Straits of Gibraltar (Sea of Alboran), between 300 and 550 m of depth. Information on the quantitative and qualitative distribution of the ostracodes was obtained, for the first time, in this area. This study also allowed to identify recall the main climatic and eustatic variations as recorded in the sediments and the faunal composition and to identify the corresponding chronological limits from the last glacial maximum to the present time. 相似文献
138.
Ricardo Gómez-Oliva Sergio Martínez-Ortega Isabel Atienza-Navarro Samuel Domínguez-García Carlos Bernal-Utrera Noelia Geribaldi-Doldán Cristina Verástegui Abdellah Ezzanad Rosario Hernández-Galán Pedro Nunez-Abades Monica Garcia-Alloza Carmen Castro 《Aging cell》2023,22(6):e13829
Neuropathological aging is associated with memory impairment and cognitive decline, affecting several brain areas including the neurogenic niche of the dentate gyrus of the hippocampus (DG). In the healthy brain, homeostatic mechanisms regulate neurogenesis within the DG to facilitate the continuous generation of neurons from neural stem cells (NSC). Nevertheless, aging reduces the number of activated neural stem cells and diminishes the number of newly generated neurons. Strategies that promote neurogenesis in the DG may improve cognitive performance in the elderly resulting in the development of treatments to prevent the progression of neurological disorders in the aged population. Our work is aimed at discovering targeting molecules to be used in the design of pharmacological agents that prevent the neurological effects of brain aging. We study the effect of age on hippocampal neurogenesis using the SAMP8 mouse as a model of neuropathological aging. We show that in 6-month-old SAMP8 mice, episodic and spatial memory are impaired; concomitantly, the generation of neuroblasts and neurons is reduced and the generation of astrocytes is increased in this model. The novelty of our work resides in the fact that treatment of SAMP8 mice with a transforming growth factor-alpha (TGFα) targeting molecule prevents the observed defects, positively regulating neurogenesis and improving cognitive performance. This compound facilitates the release of TGFα in vitro and in vivo and activates signaling pathways initiated by this growth factor. We conclude that compounds of this kind that stimulate neurogenesis may be useful to counteract the neurological effects of pathological aging. 相似文献
139.
From photosynthetic studies on a range of monocotyledonous (C-3 and C-4) and dicotyledonous (C-3) plants using a leaf oxygen electrode, we conclude the following. (i) A non-linear model [J.H.M. Thornley (1976) Mathematical models in plant physiology, Academic Press, London; B. Marshall and P.V. Biscoe (1980) J Exp Bot 31:29-39] significantly better describes the photosynthetic light response curve [rate of photosynthesis (P) versus incident photosynthetic photon flux density (I)] than the frequently used linear hyperbolic model [E.I. Rabinowich (1951) Photosynthesis and related processes, vol 2, Wiley, New York]. (ii) When used at the recommended CO2 partial pressures (Ca = 1-5 kPa), CO2 supply saturates the photosynthesis rate in the C-3 dicot Phaseolus coccineus L. but not in the C-3 monocot Hordeum vulgare L.. (iii) Fits using a linear hyperbolic model for P versus I produce relatively large and statistically significant errors (approximately 60%) in the estimation of Pmax and quantum efficiency (alpha) if Ca is not > 5 kPa. (iv) The convexity term, theta, incorporated into the non-linear models for P versus I appears to reflect the limitation placed on the carboxylation processes by the supply of CO2 to the chloroplast stroma. Therefore, the use of a non-linear model providing an estimate of theta should be encouraged, as it is likely to provide information on the physiological status of plants. 相似文献
140.
Mahmud Bani-Yaghoub Roger G Tremblay Abdellah Ajji Munyao Nzau Sandhya Gangaraju David Chitty Bogdan Zurakowski Marianna Sikorska 《Biochimie et biologie cellulaire》2008,86(5):361-369
Every year thousands of people suffer from brain injuries and stroke, and develop motor, sensory, and cognitive problems as a result of neuronal loss in the brain. Unfortunately, the damaged brain has a limited ability to enact repair and current modes of treatment are not sufficient to offset the damage. An extensive list of growth factors, neurotrophic factors, cytokines, and drugs has been explored as potential therapies. However, only a limited number of them may actually have the potential to effectively offset the brain injury or stroke-related problems. One of the treatments considered for future brain repair is bone morphogenetic protein 7 (BMP7), a factor currently used in patients to treat non-neurological diseases. The clinical application of BMP7 is based on its neuroprotective role in stroke animal models. This paper reviews the current approaches considered for brain repair and discusses the novel convergent strategies by which BMP7 potentially can induce neuroregeneration. 相似文献