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Query: UNIPROT:P06889 (Mol)
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The constants of association of seven monoclonal antibodies--each capable of binding a tetrasaccharide fragment of a linear beta(1,6)-D-galactopyranan--were measured with a series of galactosyl-ligands some of which carried deoxy-fluoro groups at selected locations. In these oligosaccharide ligands, the galactosyl residues bearing a fluorine-instead of a hydroxyl-group, cannot bind to the highest-binding subsite, which requires hydrogen-bonding. This forces a shift in the saccharide contact-residues, and in this way the relative affinities of the antibody subsites for individual galactosyl residues could be evaluated and compared with those of the four subsites investigated earlier. Correlation of sequence data, spatial structure of J 539 and binding behaviour leads to the exclusion of the third complementarity determining region (CDR) of the H-chain as partaking in the binding, and shows that the galactopyranan antigen probably binds along the lower periphery of the H-L interface of the antibodies, and does so in a groove-type fashion. Each of the seven antibodies has four subsites C, A, B and D in going from the H-to the L-chain, and the relative affinity for "their" galactosyl residue decreases in the order A greater than B greater than C greater than D. The single sugar-binding subsite A accounts for ca 50% of the total binding free energy of the maximally binding tetrasaccharide determinant in all cases.
Mol Immunol 1987 Apr
PMID:Seven structurally different murine monoclonal galactan-specific antibodies show identity in their galactosyl-binding subsite arrangements. 311 2

In order to develop imaging agents for receptor-positive tumors of the breast and prostate, we have investigated the binding affinity of several fluorine-substituted steroids in the testosterone and nortestosterone series for the androgen receptor and the progesterone receptor. The 6 alpha- and 11 beta-fluoro-, and 16 alpha-fluoroalkyl-substituted steroids were prepared by an olefin bromofluorination reaction followed by dehydrobromination or reductive debromination. The 17 alpha-fluoromethyl derivatives were prepared by fluoride ion attack on the 17-spiroepoxide or 17-spiro sulfate and the 17 alpha-fluoropropynyl derivative, by reaction of a propargyl alcohol precursor with diethylaminosulfur trifluoride. Of the compounds synthesized, 17 alpha-(3-fluoro-I-propynyl)nortestosterone was found to possess the highest binding affinity and selectivity for the progesterone receptor, and 11 beta-fluoronordihydrotestosterone had the greatest affinity for the androgen receptor. Both receptor systems seem to tolerate reasonably well the substitution of fluorine for hydrogen.
Mol Pharmacol 1987 Sep
PMID:Fluorinated androgens and progestins: molecular probes for androgen and progesterone receptors with potential use in positron emission tomography. 349 64

IgA J539 is a monoclonal anti beta-(1----6)-D-galactopyranan. Measurement of its affinity with a number of synthetic galactosyl oligosaccharides of that linkage type, in which one or more hydroxyl groups have been replaced by a fluorine atom, confirm the assignment of the relative binding strength of the subsites in the protein for the individual galactosyl residues of the antigen.
Mol Immunol 1985 Jun
PMID:Probing the combining site of monoclonal IgA J539 using deoxyfluoro- and other galactosides as ligands. 383 64

Using model systems, we have studied the properties of a number of zinc-chelating agents which are known to cause diabetes in laboratory animals. The abilities to permeate membranes and to complex zinc inside liposomes with the release of protons are suggested as chemical properties that can enhance diabetogenicity. When such complexing agents are added to lipid vesicles at pH 6 containing entrapped zinc ions, they acidify the contents of these vesicles. We have demonstrated this effect by measuring intravesicular pH both with a fluorine-containing F NMR probe as well as with the fluorescent probe, quinine. For example, using quinine, we observed that 0.1 mM 8-hydroxyquinoline reduced the intravesicular pH of sonicated phospholipid vesicles containing entrapped Zn2+ (as sulfate) from pH 6.0 to 2.8. These diabetogenic chelating agents also solubilized zinc-insulin precipitates from unbuffered suspensions at pH 6.0. The solubilization results from the acidification of these suspensions. Dithizone and 8-hydroxyquinoline at 4 mM solubilized 97 and 42%, respectively, of the suspended insulin. We suggest that if such proton release occurs within the zinc-containing insulin storage granules of pancreatic beta-cells, solubilization of insulin would be induced. Such an event would lead to osmotic stress and eventually to rupture of the granule. The effects of diethyldithiocarbamate (DDC), an agent that has been found to protect rabbits against the induction of diabetes by some other zinc-chelating agents, were also studied. DDC caused a decrease of 3.5 units in the intravesicular pH of zinc-containing vesicles by a mechanism not involving the release of protons upon chelation of zinc. We have demonstrated several properties of DDC which may contribute to its ability to protect against the induction of diabetes. These include its ability to store zinc as a hydrophobic complex in membranes, its consumption of protons upon spontaneous decomposition, and the ability of one of its decomposition products, diethylamine, to accelerate the dissipation of pH gradients across lipid bilayers. Diethylamine is particularly effective in stimulating a rapid dissipation of such pH gradients, even at micromolar concentrations. We have attempted to estimate quantitatively the extent of proton liberation by various zinc-chelating agents. This analysis demonstrated that partitioning of the ligand between organic and aqueous phases, ligand acidity, and zinc complex stability determine the extent of proton release.
Mol Pharmacol 1985 Mar
PMID:Mechanism of action of diabetogenic zinc-chelating agents. Model system studies. 388 28

To test the usefulness of immunotherapy in organophosphate poisoning, two mouse monoclonal antibodies were prepared to the chemical warfare agent soman. The antibodies bound reversibly to soman and afforded considerable protection to acetylcholinesterase in vitro. However, they were only marginally effective in preventing the consequences of soman poisoning in mice (these data have been published elsewhere). Since potential for immunotherapeutic usefulness resides in antibody affinity and specificity, we conducted experiments to define these parameters to enable us to maximize them in the production of later antibodies. Interaction of the antibodies (CC1 and BE2) in affinity-purified form with a series of soman analogs in a competitive inhibition enzyme immunoassay was used to assess the contribution to binding affinity of each functional group on the soman molecule. Neither antibody interacted with the -P = S analog of soman or methylphosphonic acid. A decrease in the number of methyl groups on the pinacolyl side chain reduced or eliminated binding with both antibodies while increasing the size of this group had a mixed result. The major metabolite of soman, its basic hydrolysis product, interacted weakly with BE2 and failed to interact with CC1. Alkyl ester group substitution at the fluorine position increased antibody binding up to the symmetrical dipinacolyl analog. Stereochemical specificity was determined by measuring the apparent decrease in the rate of inhibition of cholinesterases (acetylcholine acetylhydrolase, EC 3.1.1.7, or acylcholine acylhydrolase, EC 3.1.1.8) by pure soman stereoisomers in the presence of increasing concentrations of each antibody. CC1 demonstrated specificity that varied as C(+)P(+) less than C(-)P(+) less than C(-)P(-) less than C(+)P(-). Although affinities were much lower, BE2 also showed a preference for the more toxic P(-) isomers.
Mol Pharmacol 1985 Jul
PMID:Structural and stereochemical specificity of mouse monoclonal antibodies to the organophosphorous cholinesterase inhibitor soman. 402 95

2'-Fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC) is a potent antiviral agent with minimal cytotoxicity. In Vero cells, incorporation of labeled dCyd and dThd into the acid-insoluble DNA fraction was, respectively, competitively and noncompetitively inhibited by FIAC. In herpes simplex type 1 (HSV-1) infected Vero cells, these inhibition patterns became noncompetitive. The inhibition constants of FIAC on dThd and dCyd incorporation into the acid-insoluble fraction during a 15-min period were greater than 30 microM which were much higher than the antiviral concentration of FIAC (ED90 = 0.003-0.013 microM) for continuous exposure. Incorporation of dUrd into acid-insoluble DNA was inhibited by 10 microM FIAC in HSV-1-infected Vero cells, but not in uninfected cells. The radioactivity of [2-14C]FIAC was incorporated into the acid-insoluble DNA fraction, and this incorporation in uninfected cells was strongly inhibited by 10 microM dCyd but not by dThd. By contrast, the incorporation in HSV-1-infected Vero cells was strongly inhibited by 10 microM dThd but not by dCyd. These data indicate that FIAC behaves metabolically like dThd, dUrd, or 5-iodo-dUrd in HSV-1-infected cells but like dCyd in noninfected cells. Thus, combined use of dCyd and FIAC may reduce cytotoxicity of FIAC or incorporation of FIAC into host cell DNA without affecting its antiviral activity. This finding is of significance since, for practical reasons, incorporation of FIAC into host cell DNA needs to be reduced as much as possible.
Mol Pharmacol 1984 Nov
PMID:Metabolic competition studies of 2'-fluoro-5-iodo-1-beta-d-arabinofuranosylcytosine in vero cells and herpes simplex type 1-infected vero cells. 609 4

Female rats were given 150 ppm fluoride in the drinking water during three successive pregnancy and lactation periods; the femoral diaphyses were then examined for morphological alterations by light and scanning electron microscopy to determine the influence of fluoride ingestion during multiple pregnancies and lactations. The periosteal surface was dominated by areas of woven bone formation with some prolonged resting areas around osteocyte lacunae. The endosteal surface consisted mainly of areas of active bone resorption with some areas of bone formation. The interior of the cortex was characterized by numerous resorption cavities and remodeling in secondary Haversian systems. Fluoride, by the nature of its incorporation into bone crystals and by its direct cytotoxic effect on bone resorbing cells, reduces the availability of calcium from bone. It appears that fluoride ingestion during lactation created a heightened state of calcium homeostatic stress. As a result, bone mineral was mobilized by resorption of the endosteal surface and by cavitation of the interior of the cortex. Secondary hyperparathyroidism is thought to play an integral part in an attempt to maintain calcium homeostasis.
Virchows Arch B Cell Pathol Incl Mol Pathol 1983
PMID:Fluoride ingestion during multiple pregnancies and lactations: microscopic observations on bone of the rat. 613 92

Fluoride and peptide-stimulated adenylate cyclase activity was investigated by electron histochemistry on serial sections of the RPAI neuron of the snail Helix pomatia. Fluoride-stimulated adenylate cyclase was detected in the surface membrane of the RPAI neuron, the postsynaptic membrane of axosomatic contacts, and the surface of glial cells forming a multilayer capsule around the neuron. Peptide-stimulated adenylate cyclase was located in the membrane of glial cells surrounding the neuron, their processes (trophospongia) invaginating deeply in the neuronal soma, and the membrane of somatic protrusions forming the system of lacoons in the region of the axosomatic contact. No peptide-stimulated adenylate cyclase was revealed in the remaining part of the surface of the somatic membrane. The localization of adenylate cyclase activity in the postsynaptic membrane in the region of the axosomatic contact is in accordance with the hypothesis based on electrophysiological experiments that the cyclase system participates in the genesis and regulation of the bursting activity of the RPAI neuron.
Cell Mol Neurobiol 1984 Mar
PMID:The axosomatic contacts on the bursting neuron of the snail Helix pomatia. II. Ultrastructural localization of adenylate cyclase. 620 58

5-Fluoro-5'-O-nitro-2'-deoxyuridine (FdUMN), a neutral isostere of 5-fluoro-2'-deoxyuridine 5'-monophosphate, inhibited the growth of L1210 cultures. The inhibition of L1210 cultures by FdUMN was prevented by thymidine, but not by 2'-deoxyuridine. Like 5-fluoro-2'-deoxyuridine (FdUrd), FdUMN inhibited the incorporation of 2'-deoxyuridine into DNA, but the onset of this inhibition was not immediate, as was seen with FdUrd. FdUMN did not inhibit the activity of purified thymidylate synthetase from Lactobacillus casei and was a poor inhibitor of thymidylate synthetase activity in homogenates of L1210 ascites cells. However, after incubation with homogenates of these cells and subsequent addition of ATP, FdUMN inhibited this enzyme effectively. These results indicate that intracellular activation of FdUMN is required for its inhibition of thymidylate synthetase.
Mol Pharmacol 1982 Nov
PMID:Cytotoxicity of 5-fluoro-5'-O-nitro-2'-deoxyuridine, a new fluorinated pyrimidine derivative, in L1210 cultures. 621 91

Fluorine-19 nuclear magnetic resonance has been used to investigate the histidine-binding protein J from Salmonella typhimurium. The protein has been labeled with fluorine-19 by growing the bacterial cells of a tryptophan auxotroph in the presence of 5-fluorotryptophan. Incorporation of up to 70% was achieved. The binding of L-histidine to the 19F-labeled protein is not affected by the isotopic labeling. The protein contains one tryptophan residue, giving rise to a single 19F resonance. Upon binding L-histidine to 19F-labeled histidine-binding protein J, the observed 19F resonance is shifted downfield by about 0.6 parts per million, indicating a conformational change of the protein molecule and a more hydrophobic environment for the 19F nucleus. Additional fluorescence experiments confirm that the tryptophan residue is located inside the hydrophobic core of the protein. 19F spin-lattice relaxation times of the 19F-labeled protein as a function of temperature show no difference between the free protein and the protein-histidine complex. However, the linewidth for the free protein is much larger than that of the protein-substrate complex. This can be explained by slow fluctuations between different conformations of the free protein molecule having slightly different 19F chemical shifts. Both with and without the substrate, the tryptophan residue is immobile inside the protein molecule as shown by the total disappearance of the 19F signal upon broadband irradiation at the 1H frequency. Also, the 19F spin-lattice relaxation times indicate that the protein is a rather rigid structure, in which rapid motions of the tryptophan residue on the time scale of 10(-8) second are not prominent.
J Mol Biol 1984 Nov 15
PMID:Fluorine-19 nuclear magnetic resonance study of 5-fluorotryptophan-labeled histidine-binding protein J of Salmonella typhimurium. 638 86


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