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101.
Inhibition of angiotensin I-converting enzyme (ACE) has become an effective strategy in the treatment of hypertension and cardiovascular disease. Keto-ACE, a previously described C-domain selective ACE inhibitor, was used as the basis for the design, synthesis and molecular modelling of a series of novel ketomethylene derivatives for which ACE inhibition profiles and structural characterisation are reported. Ki determinations indicated that the introduction of a bulky aromatic tryptophan at the P2' position of keto-ACE significantly increased selectivity for the C-domain, while an aliphatic P2 Boc group conferred N-domain selectivity. These data were supported by the potential energies of the compounds docked with the C- and N-domains of ACE. 相似文献
102.
This is a correction article 相似文献
103.
Current population-based schistosomiasis treatment programs are a first step to reducing the global burden of Schistosoma-related disease; however, they might not dramatically reduce parasite transmission in highly endemic areas. Consequently, the benefits of these programs remain in doubt because recurring low-level reinfection is likely to be associated with subtle but persistent morbidities such as anemia, undernutrition and diminished performance status. The real health benefits of transmission control need to be reconsidered and attention given to more aggressive and, ultimately, more affordable parasite elimination strategies. The next generation of schistosomiasis control can be optimized using new monitoring tools and effective transmission containment. 相似文献
104.
J
RGEN STENVIK METTE SERINE WESMAJERVI KJERSTI TURID FJALESTAD B
RGE DAMSGRD MADJID DELGHANDI 《Molecular ecology resources》2006,6(4):1105-1107
Microsatellites were identified by screening 2294 GenBank entries available for Atlantic cod (Gadus morhua L.), mainly representing expressed sequence tags and cDNA sequences. Ninety‐two novel microsatellite loci (tetra‐, tri‐ and dinucleotides) were characterized on 96 individuals. This strategy yielded 25 gene‐associated polymorphic microsatellite markers (11 tri‐ and 14 dinucleotides) with two to 20 alleles and an average heterozygosity of 0.48 in the population studied (range 0.02–0.89). One marker exhibited significant homozygote excess, and one of the primer pairs amplified two linked markers. The gene identity was determined at nine of the loci, confirming the associated microsatellites as type I markers. 相似文献
105.
Colin S. Anthony Hazel R. Corradi Sylva L. U. Schwager Pierre Redelinghuys Dimitris Georgiadis Vincent Dive K. Ravi Acharya Edward D. Sturrock 《The Journal of biological chemistry》2010,285(46):35685-35693
Angiotensin-I-converting enzyme (ACE) plays a critical role in the regulation of blood pressure through its central role in the renin-angiotensin and kallikrein-kinin systems. ACE contains two domains, the N and C domains, both of which are heavily glycosylated. Structural studies of ACE have been fraught with severe difficulties because of surface glycosylation of the protein. In order to investigate the role of glycosylation in the N domain and to create suitable forms for crystallization, we have investigated the importance of the 10 potential N-linked glycan sites using enzymatic deglycosylation, limited proteolysis, and mass spectrometry. A number of glycosylation mutants were generated via site-directed mutagenesis, expressed in CHO cells, and analyzed for enzymatic activity and thermal stability. At least eight of 10 of the potential glycan sites are glycosylated; three C-terminal sites were sufficient for expression of active N domain, whereas two N-terminal sites are important for its thermal stability. The minimally glycosylated Ndom389 construct was highly suitable for crystallization studies. The structure in the presence of an N domain-selective phosphinic inhibitor RXP407 was determined to 2.0 Å resolution. The Ndom389 structure revealed a hinge region that may contribute to the breathing motion proposed for substrate binding. 相似文献
106.
107.
Akif M Schwager SL Anthony CS Czarny B Beau F Dive V Sturrock ED Acharya KR 《The Biochemical journal》2011,436(1):53-59
Human ACE (angiotensin-I-converting enzyme) has long been regarded as an excellent target for the treatment of hypertension and related cardiovascular diseases. Highly potent inhibitors have been developed and are extensively used in the clinic. To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zinc metallopeptidase (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and ECE-1 (endothelin-converting enzyme-1). In the present paper, we show the first structures of testis ACE [C-ACE, which is identical with the C-domain of somatic ACE and the dominant domain responsible for blood pressure regulation, at 1.97? (1 ?=0.1 nm)] and the N-domain of somatic ACE (N-ACE, at 2.15?) in complex with a highly potent and selective dual ACE/ECE-1 inhibitor. The structural determinants revealed unique features of the binding of two molecules of the dual inhibitor in the active site of C-ACE. In both structures, the first molecule is positioned in the obligatory binding site and has a bulky bicyclic P(1)' residue with the unusual R configuration which, surprisingly, is accommodated by the large S(2)' pocket. In the C-ACE complex, the isoxazole phenyl group of the second molecule makes strong pi-pi stacking interactions with the amino benzoyl group of the first molecule locking them in a 'hand-shake' conformation. These features, for the first time, highlight the unusual architecture and flexibility of the active site of C-ACE, which could be further utilized for structure-based design of new C-ACE or vasopeptidase inhibitors. 相似文献
108.
Matrix metalloproteinases (MMPs) cleave and degrade most components of the extracellular matrix, and unregulated MMP activity has been correlated to cancer and metastasis. Hence there is a burgeoning need to develop inhibitors that bind selectively to structurally similar MMPs. The inhibition profiles of peptidomimetics containing C(α) substituents at the α,β unsaturated carbon were evaluated against the recombinant forms of ADAM17, MMP1, and MMP9. The dicarboxylic acid D2 and hydroxamate C2 inhibited MMP9 but not MMP1. The unsaturated compound E2 displayed selective inhibition for MMP1, compared with the saturated precursor C2, with an IC(50) value of 3.91 μm. The molecular basis for this selectivity was further investigated by the molecular docking of E2 and D2 into the active sites of MMP1 and MMP9. These data demonstrate hydrogen-bonding interactions between the carbonyl group of the C(α) substituent of E2 and the side chain of Asn180 present in the active site of MMP1. Conversely, the docked MMP9-D2 structure shows hydrophobic and hydrogen bonding between the ligand's morpholine substituent and second carboxylic acid group with Leu187 and an amide, respectively. This study suggests that substituents other than P(1)' and P(2)' may confer selectivity among MMPs and may aid in the search for novel lead compounds. 相似文献
109.
In the vertebrate embryo, tissue blocks called somites are laid down in head-to-tail succession, a process known as somitogenesis. Research into somitogenesis has been both experimental and mathematical. For zebrafish, there is experimental evidence for oscillatory gene expression in cells in the presomitic mesoderm (PSM) as well as evidence that Notch signalling synchronises the oscillations in neighbouring PSM cells. A biological mechanism has previously been proposed to explain these phenomena. Here we have converted this mechanism into a mathematical model of partial differential equations in which the nuclear and cytoplasmic diffusion of protein and mRNA molecules is explicitly considered. By performing simulations, we have found ranges of values for the model parameters (such as diffusion and degradation rates) that yield oscillatory dynamics within PSM cells and that enable Notch signalling to synchronise the oscillations in two touching cells. Our model contains a Hill coefficient that measures the co-operativity between two proteins (Her1, Her7) and three genes (her1, her7, deltaC) which they inhibit. This coefficient appears to be bounded below by the requirement for oscillations in individual cells and bounded above by the requirement for synchronisation. Consistent with experimental data and a previous spatially non-explicit mathematical model, we have found that signalling can increase the average level of Her1 protein. Biological pattern formation would be impossible without a certain robustness to variety in cell shape and size; our results possess such robustness. Our spatially-explicit modelling approach, together with new imaging technologies that can measure intracellular protein diffusion rates, is likely to yield significant new insight into somitogenesis and other biological processes. 相似文献
110.
Mir-Kasimov M Sturrock A McManus M Paine R 《American journal of physiology. Lung cellular and molecular physiology》2012,302(6):L504-L511
Local pulmonary expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) is critically important for defense of the pulmonary alveolar space. It is required for surfactant homeostasis and pulmonary innate immune responses and is protective against lung injury and aberrant repair. Alveolar epithelial cells (AEC) are a major source of GM-CSF; however, the control of homeostatic expression of GM-CSF is incompletely characterized. Increasing evidence suggests considerable plasticity of expression of AEC phenotypic characteristics. We tested the hypothesis that this plasticity extends to regulation of expression of GM-CSF using 1) MLE-12 cells (a commonly used murine cell line expressing some features of normal type II AEC, 2) primary murine AEC incubated under standard conditions [resulting in rapid spreading and loss of surfactant protein C (SP-C) expression with induction of the putative type I cell marker (T1α)], or 3) primary murine AEC on a hyaluronic acid/collagen matrix in defined medium, resulting in preservation of SP-C expression. AEC in standard cultures constitutively express abundant GM-CSF, with further induction in response to IL-1β but little response to TNF-α. In contrast, primary cells cultured to preserve SP-C expression and MLE-12 cells both express little GM-CSF constitutively, with significant induction in response to TNF-α and limited response to IL-1β. We conclude that constitutive and cytokine-induced expression of GM-CSF by AEC varies in concert with other cellular phenotypic characteristics. These changes may have important implications both for the maintenance of normal pulmonary homeostasis and for the process of repair following lung injury. 相似文献