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31.
Junqing Guo Andrew Watson James Kempson Marianne Carlsen Joseph Barbosa Karen Stebbins Deborah Lee John Dodd Steven G. Nadler Murray McKinnon Joel Barrish William J. Pitts 《Bioorganic & medicinal chemistry letters》2009,19(7):1935-1938
A series of pyrimidine based inhibitors of PDE7 are discussed. The synthesis, structure–activity relationships (SAR) and selectivity against several other PDE family members as well as activity in T cells are presented. These compounds were found to have effects on T cell proliferation, however it is not clear whether the mechanism is related to PDE7 inhibition. 相似文献
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Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics 总被引:1,自引:0,他引:1
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Killer cell immunoglobulin-like receptors (KIR) inhibit the cytotoxic activity of natural killer (NK) cells by recruitment of the tyrosine phosphatase SHP-1 to immunoreceptor tyrosine-based inhibition motif (ITIM) sequences in the KIR cytoplasmic tail [1]. The precise steps in the NK activation pathway that are inhibited by KIR are yet to be defined. Here, we have studied whether the initial step of adhesion molecule LFA-1-dependent adhesion to target cells was altered by the inhibitory signal. Using stable expression of an HLA-C-specific KIR in the NK cell line YTS [2] and a two-color flow cytometry assay for conjugate formation, we show that adhesion to a target cell expressing cognate HLA-C was disrupted by KIR engagement. Conjugate formation was abruptly interrupted by KIR within less than 5 minutes. Inhibition of adhesion to target cells was mediated by a chimeric KIR molecule carrying catalytically active SHP-1 in place of its cytoplasmic tail. These results suggest that other ITIM-bearing receptors, many of which have no known function, may regulate adhesion in a wide variety of cell types. 相似文献
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Recent x-ray crystallographic studies of aspartate transcarbamoylase bound with CTP have detected molecular asymmetry in the interface between the catalytic and regulatory subunits (Kim, K. H., Pan, Z., Honzatko, R. B., Ke, H.-M., and Lipscomb, W. N. (1987) J. Mol. Biol. 196, 863-875). In three of the six interfaces, a salt link occurs between Arg130 of the regulatory chain and Glu204 of the catalytic chain; however, these same residues are 15 A apart in the other three interfaces. In order to determine if this is important for the function of the enzyme, two mutant versions of aspartate transcarbamoylase were created by site-specific mutagenesis. Glu204 of the catalytic chain was converted to a glutamine (Glu204c----Gln) and Arg130 of the regulatory chain was converted to a glycine (Arg130r----Gly). The thermal stability of the Arg130r----Gly enzyme is dramatically reduced, whereas the thermal stability of the Glu204c----Gln enzyme is unaltered compared to the wild-type enzyme. The maximal velocity of both mutant enzymes is identical with that of the wild-type enzyme, however both mutant enzymes have altered substrate affinity and regulatory properties. Based on these studies, the link between Glu204 of the catalytic chain and Arg130 of the regulatory chain is important for the heterotropic properties of the enzyme. Furthermore, the interface between the domain of the regulatory chain which binds zinc and the domain of the catalytic chain which binds aspartate may be more important for CTP inhibition than ATP activation. These data also suggest that heterotropic cooperativity is very sensitive to alterations in the catalytic-regulatory interface. However, no clear relationship has been observed between the structural asymmetry and the function of the enzyme. 相似文献
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