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131.
132.
Kempson J Pitts WJ Barbosa J Guo J Omotoso O Watson A Stebbins K Starling GC Dodd JH Barrish JC Felix R Fischer K 《Bioorganic & medicinal chemistry letters》2005,15(7):1829-1833
A series of fused pyrimidine based inhibitors of PDE7 have been derived from an earlier screening lead 1. The synthesis, structure-activity relationships (SAR) and selectivity against several other PDE family members are described. 相似文献
133.
The helix-loop-helix (i.e., EF-hand) Ca(2+) ion binding motif is characteristic of a large family of high-affinity calcium ion binding proteins, including the parvalbumins, oncomodulins and calmodulins. In this work we describe a set of molecular dynamics computations on the major parvalbumin from the silver hake (SHPV-B) and on functional fragments of this protein, consisting of the first four helical regions (the ABCD fragment), and the internal helix-loop- helix region (the CD fragment). In both whole protein and protein fragments (i.e., ABCD and CD fragments), the 9th loop residue in the calcium ion binding site in the CD helix-loop-helix region (the so-called "gateway" position) has been mutated from glutamic acid to aspartic acid. Aspartic acid is one of the most common residues found at the gateway position in other (non-parvalbumin) EF- hand proteins, but has never been found at the gateway position of any parvalbumin. (Interestingly, aspartic acid does occur at the gateway position in the closely related rat and human oncomodulins.) Consistent with experimental observations, the results of our molecular dynamics simulations show that incorporation of aspartic acid at the gateway position is very disruptive to the structural integrity of the calcium ion coordination site in the whole protein. The aspartic acid mutation is somewhat less disruptive to the calcium ion coordination sites in the two parvalbumin fragments (i.e., the ABCD and CD fragments), presumably due to the higher degree of motional freedom allowable in these protein fragments. One problem associated with the E59D whole protein variant is a prohibitively close approach of the aspartate carboxyl group to the CD calcium ion observed in the energy-minimized (pre-molecular dynamics) structure. This steric situation does not emerge during energy-minimization of the wild-type protein. The damage to the structural integrity of the calcium ion coordination site in the whole protein E59D variant is not relieved during the molecular dynamics simulation. In fact, during the course of the 300 picosecond simulation, all of the calcium ion ligands leave the primary coordination sphere. In addition, the conserved hydrogen- bonds (in the short beta-sheet structure) that links the CD site to the symmetry-related EF site (in the non-mutated whole protein) is also somewhat disrupted in the E59D whole protein variant. These results suggest that the Ca(2+) ion binding deficiencies in the CD loop are related, at least in part, to the unique interaction that exists between the paired CD and EF hands in the whole protein. Our theoretical results correlate well with previous studies on engineered EF-hand proteins and with all of our experimental evidence on whole silver hake parvalbumin and enzymatically-generated parvalbumin fragments. 相似文献
134.
Gomulski LM Pitts RJ Costa S Saccone G Torti C Polito LC Gasperi G Malacrida AR Kafatos FC Zwiebel LJ 《Genetics》2001,157(3):1245-1255
An approximately 14-kb region of genomic DNA encoding the wild-type white eye (w+) color gene from the medfly, Ceratitis capitata has been cloned and characterized at the molecular level. Comparison of the intron-exon organization of this locus among several dipteran insects reveals distinct organizational patterns that are consistent with the phylogenetic relationships of these flies and the dendrogram of the predicted primary amino acid sequence of the white loci. An examination of w+ expression during medfly development has been carried out, displaying overall similarity to corresponding studies for white gene homologues in Drosophila melanogaster and other insects. Interestingly, we have detected two phenotypically neutral allelic forms of the locus that have arisen as the result of an apparently novel insertion or deletion event located in the large first intron of the medfly white locus. Cloning and sequencing of two mutant white alleles, w1 and w2, from the we,wp and M245 strains, respectively, indicate that the mutant conditions in these strains are the result of independent events--a frameshift mutation in exon 6 for w1 and a deletion including a large part of exon 2 in the case of w2. 相似文献
135.
A rapid solution immunoassay to quantify binding of the human immunodeficiency virus envelope glycoprotein to soluble CD4 总被引:1,自引:0,他引:1
T J McQuade T W Pitts W G Tarpley 《Biochemical and biophysical research communications》1989,163(1):172-176
We developed a particle concentration fluorescent immunoassay to quantify the binding in solution of the human immunodeficiency virus (HIV) external glycoprotein (gp120) to soluble CD4 (sCD4). The assay is rapid (1 hr), quantitative, and requires as little as 0.1 pmole of gp120 per evaluation. We find that gp120, purified from recombinant baculovirus infected insect cells, is suitable for the assay. Moreover, sCD4s obtained either from recombinant E. coli or mammalian cells, consisting of the N-terminal two domains (about 180 amino acids) as well as linked to the active regions of Pseudomonas exotoxin A, bind gp120 similarly. 相似文献
136.
Epithelial cells were separated from suspensions of hamster parotid cells by velocity sedimentation in an isokinetic gradient and by isopycnic sedimentation. Epithelial cells were 48.1 ± 18.0% of the cells in the starting sample suspensions of cells from the disaggregated hamster parotid glands. The purest gradient fractions following velocity sedimentation in a previously described isokinetic gradient contained 98.8 ± 1.8% epithelial cells. The purest fractions obtained from isopycnic sedimentation contained 99.9 ± 0.2% epithelial cells. Purification of parotid epithelial cells by velocity sedimentation in the isokinetic gradient seems preferable to purification using isopycnic centrifugation because a larger proportion of the epithelial cells are obtained in the zone of the gradient which contains highly purified epithelial cells and because velocity sedimentation requires lower centrifugal forces for a shorter period of time. 相似文献
137.
A pure, enzymatically active Ca2+-dependent adenosine triphosphatase (Ca2+-ATPase) has been isolated from canine ventricular sarcoplasmic reticulum. In contrast to that derived from skeletal muscle, the Ca2+-ATPase from cardiac sarcoplasmic reticulum was more active when solubilization and subsequent purification took place in the presence of its substrates, Ca2+ and ATP. Cholate- or deoxycholate-solubilized Ca2+-ATPase is recovered following rapid glycerol dilution and centrifugation. The Ca2+-ATPase is stable and possesses hydrolytic capacities up to 4 mumol/mg/min. Sodium dodecyl sulfate-polyacrylamide gels reveal the presence of one protein in the range of 95,000 to 100,000 daltons. This method also yields purified Ca2+-ATPase from fast skeletal muscle of similar activities to those reported by other laboratories. 相似文献
138.
Visual acuity and contrast sensitivity progressively diminish with increasing viewing eccentricity. Here we evaluated how visual enumeration is affected by visual eccentricity, and whether subitizing capacity, the accurate enumeration of a small number (~3) of items, decreases with more eccentric viewing. Participants enumerated gratings whose (1) stimulus size was constant across eccentricity, and (2) whose stimulus size scaled by a cortical magnification factor across eccentricity. While we found that enumeration accuracy and precision decreased with increasing eccentricity, cortical magnification scaling of size neutralized the deleterious effects of increasing eccentricity. We found that size scaling did not affect subitizing capacities, which were nearly constant across all eccentricities. We also found that size scaling modulated the variation coefficients, a normalized metric of enumeration precision, defined as the standard deviation divided by the mean response. Our results show that the inaccuracy and imprecision associated with increasing viewing eccentricity is due to limitations in spatial resolution. Moreover, our results also support the notion that the precise number system is restricted to small numerosities (represented by the subitizing limit), while the approximate number system extends across both small and large numerosities (indexed by variation coefficients) at large eccentricities. 相似文献
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140.