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V Cody

Publications and source records attributed to V Cody.

At least 19 recordsLinked to original sources
PubMed1992

Crystal structure determination at 2.3-A resolution of human transthyretin-3',5'-dibromo-2',4,4',6-tetrahydroxyaurone complex.

The crystal structure of the complex of 3',5'-dibromo-2',4,4',6-tetrahydroxyaurone, a flavone derivative, with human transthyretin (TTR), a serum thyroid hormone transport protein, has been determined and refined to R = 17.9% for data to 2.3-A resolution and provides a detailed description of a protein-bound flavonoid structure. This bromoaurone is a potent competitor for thyroid hormone binding to TTR, a 54,980-dalton alpha 4 tetrameric protein of 222 molecular symmetry, as well as an inhibitor of iodothyronine deiodinase. Crystals of the TTR-bromoaurone complex are isomorphous to those of native TTR. Interpretation of difference Fourier electron density maps revealed two binding modes for the bromoaurone in each of the two independent binding sites of the TTR tetramer: deep in the channel near Ser-117 (mode I) and near the channel entrance (mode II). None of the binding modes can be fully occupied because of overlap between binding positions. A statistical disorder for bromoaurone binding was also applied, as it binds along the twofold crystallographic axis and does not possess such symmetry. The binding of mode I and that of mode II were refined at half occupancy, resulting in two molecules per tetramer. The bromoaurone binds in a nonplanar antiskewed conformation. The molecular pattern for TTR binding consists of halogen groups able to anchor between beta-sheets to form both hydrophobic and hydrophilic contacts. Comparison of structural data for bromoaurone- and thyroxine-TTR complexes indicates that bromoaurone binding mode I is 3 A deeper in the channel and binding mode II is 4 A further from the channel center than thyroxine. The bromoaurone binding observed in this TTR complex differs significantly from that based upon computer modeling studies.

Benzofurans↗
PubMed1992

Purification and crystallization of Lactobacillus casei folylpolyglutamate synthetase expressed in Escherichia coli.

Folylpolyglutamate synthetase (FPGS) from Lactobacillus casei has been crystallized with polyethylene glycol and acetate buffer at pH 5.0. The enzyme was obtained from Escherichia coli strain SF4 harboring the L. casei FPGS chromosomal gene on a pEMBL vector (pGT3-8.1). Crystals of the enzyme were obtained which diffract to 2.6 A resolution. The crystals are monoclinic, space group P2(1), with unit cell dimensions of a = 54.07 A, b = 45.83 A, c = 84.37 A and beta = 107.92 degrees. A unit cell contains one molecule of the 43,000 Da enzyme per asymmetric unit. A complete X-ray data set on the native crystals has been collected.

Escherichia coli↗
PubMed1992

Mechanism of molecular recognition. Structural aspects of 3,3'-diiodo-L-thyronine binding to human serum transthyretin.

The three-dimensional structure of the thyroid hormone metabolite, 3,3'-diiodo-L-thyronine (3,3'-T2), complex with human serum transthyretin (TTR) has been refined to R = 18.5% for 8-2 A resolution data. This is the first detailed description of a thyroid hormone metabolite binding to a thyroid transport protein. The four TTR monomeric subunits form a tetramer in the same manner as the native transthyretin reported earlier (Blake, C. C. F., Geisow, M. J., Oatley, S. J., Rerat, B., and Rerat, C. (1978) J. Mol. Biol. 121, 339-356). The two hormone binding sites of the TTR tetramer are occupied by 3,3'-T2. A statistical disorder model for the ligand was applied with a 50% occupancy to account for the discrepancy between the crystallographic 2-fold symmetry of the binding sites and the lack of such symmetry for 3,3'-T2. The bound metabolite has an overall transoid conformation with the either bridge intermediate between skewed and perpendicular. The hormone metabolite is bound 3.5 A deeper and with a different orientation in the channel than observed for thyroxine (T4), thereby revealing the presence of another set of halogen binding sites close to the center of the tetramer. When compared with the binding of T4, these data show that the 3-iodine of 3,3'-T2 occupies the same site as the 3'-iodine of T4, and the metabolite 3'-iodine occupies the water site observed in the T4 complex. The binding affinity of 3,3'-T2, which is 100-fold lower than that of T4, reflects the lack of the second pair of iodine atoms interacting in the channel. In order to understand the tighter binding of T4 observed in the Ala-109----Thr mutant, modeling studies were carried out that indicate that this modification could shorten the contacts between thyroid hormone iodines and residues 108-110 of the binding site.

Binding Sites↗
PubMed1992

Absolute configuration and conformation of the pure opioid antagonist (+)-2,9 alpha-dimethyl-5-(m-hydroxyphenyl)morphan.

(+)-2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan is the only phenylmorphan analog whose affinity for opioid kappa-receptors is greater than its affinity for opioid mu-receptors. Pharmacologically, the compound is a pure opioid antagonist devoid of agonist activity in in vivo assays of antinociception. The absolute configuration of the compound has been determined to be (1R,5S,9R) from an X-ray crystallographic study of the chloride salt. Thus, the absolute configuration corresponds to that of the atypical opioid agonist (-)-phenylmorphan while the weak atypical agonist (-)-2,9 alpha-dimethyl-5-(m- hydroxyphenyl)morphan corresponds to the potent morphine-like (+)-phenylmorphan. The preferred orientations of the phenyl ring for the two stereoisomers were determined using the molecular mechanics program MM2-87 and found to vary from that of the two parent compounds. The atypical properties of the two 9 alpha-methyl analogs is consistent with an opioid ligand model which proposes that morphine-like properties require a particular range of phenyl orientations. There was good agreement between the structure obtained from X-ray crystallography and computed with the MM2-87 program.

Chemical Phenomena↗
PubMed1992

Purification and crystallization of insecticidal delta-endotoxin CryIIIB2 from Bacillus thuringiensis.

CryIIIB2, an insecticidal protein from Bacillus thuringiensis has been crystallized from 0.6 M NaBr and HEPES buffer at pH 7.0 and X-ray diffraction data collected on a native crystal to 2.4 A. The insecticidal protein was obtained from a Bacillus thuringiensis (Bt) strain EG7231. Crystals of the endotoxin are orthorhombic, space group C2221, with unit cell dimensions of a = 122.44, b = 131.81, and c = 105.37 A. A unit cell contains one molecule of the 67,000 Da endotoxin per asymmetric unit.

Bacillus thuringiensis↗
PubMed1992

Crystal structure determination at 2.3 A of recombinant human dihydrofolate reductase ternary complex with NADPH and methotrexate-gamma-tetrazole.

The crystal structure of the methotrexate-gamma-tetrazole (MTXT)-NADPH ternary complex with recombinant human dihydrofolate reductase (DHFR) has been determined and refined to R = 15.9% for 7003 data from 10.0 to 2.3 A resolution for the R3 lattice. Interpretation of difference Fourier electron density maps revealed that the cofactor NADPH is bound in an extended conformation, and the closest contact between cofactor and inhibitor is 3.1 A, between N(5) of the MTXT pteridine ring and the nicotinamide C(4) which transfers a hydride during the enzyme-catalyzed reaction. As in other DHFR complexes, MTXT is interpreted as protonated at N(1) by Glu-30, and the 2-amino group is hydrogen bonded to a structurally conserved water which also interacts with Glu-30 and Thr-136. The 4-amino group of MTXT hydrogen bonds to the carbonyl of Ile-7 and the phenolic hydroxyl of Tyr-121, and the alpha-carboxylate forms a salt bridge with the conserved Arg-70. In this structure, the amide carbonyl forms two hydrogen bonds with Asn-64 and a water molecule, whereas the gamma-tetrazole ring does not interact directly with the enzyme. The largest changes in the secondary structure on formation of the ternary complex involve the fold of a flexible loop near residues 40-46, and to a lesser extent the helical region near residues 102-109 and the beta-sheet regions near residues 71-75 and 157-159.

Crystallography↗
PubMed1991

Structure of 6-oxo-1,6-dihydro-3,4'-bipyridine-5-carbonitrile hydrogen bromide.

5-Cyano-6-oxo-1,6-dihydro-3,4'-bipyridinium bromide, C11H8N3O+.Br-, Mr = 278.11, triclinic, P1, a = 7.827 (2), b = 9.796 (2), c = 15.548 (4) A, alpha = 76.53 (2), beta = 75.40 (2), gamma = 74.36 (2) degrees, V = 1093.4 (4) A3, Z = 4, Dx = 1.689 Mg m-3, lambda (Mo K alpha) = 0.71073 A, mu = 3.70 mm-1, F(000) = 552, T = 293 K, R = 0.084 for 3989 observed reflections. The bipyridinium ions are planar, the C(2)-C(1)-C(1')-C(2') torsion angles being -3.3 (10) and 2.2 (11) degrees for molecules (1) and (2), respectively. The symmetry-independent bipyridinium ions are assembled in separate chains by hydrogen-bonding Br bridges [respective distances: Br(1)...N(3) 3.227 (6); Br(1)...N(4') 3.374 (6); Br(2)...N(3*) 3.263 (5); Br(2)...N(4'*) 3.540 (7) A] and by forming N...O hydrogen bonds between pyridinium NH groups and keto O atoms, the N(4')...O(4) and N(4'*)...O(4') distances being 2.835 (7) and 2.706 (7) A, respectively. These chains are connected by the series of stacking interactions with an average C...C distance of 3.5 A.

Cardiotonic Agents↗
PubMed1991

Structure of two polymorphs of 2-methyl-3,4'-bipyridin-6(1H)-one.

C11H10N2O, Mr = 186.22. Polymorph (I) monoclinic, P2(1)/c, a = 7.574 (1), b = 11.132 (2), c = 11.437 (2) A, beta = 94.90 (1) degree, V = 960.8 (5) A3, Z = 4, Dx = 1.287 Mg m-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.079 mm-1, F(000) = 392, T = 293 K, R = 0.058 for 2335 observed reflections. Polymorph (II) monoclinic, P2(1)/c, a = 6.7897 (7), b = 13.449 (2), c = 10.736 (1) A, beta = 108.644 (8) degrees, V = 928.9 (2) A3, Z = 4, Dx = 1.331 Mg m-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.082 mm-1, F(000) = 392, T = 293 K, R = 0.047 for 1952 observed reflections. The molecular conformations in the two polymorphs are similar and the torsion angle C(2)--C(1)--C(1')--C(2') is 58.9 (2) and 54.1 (2) degrees for (I) and (II), respectively. Both structures contain centrosymmetric hydrogen-bonded dimers of molecules with the pyridone ring NH groups acting as donors and the keto O atoms as acceptors with N...O distances of 2.776 (2) and 2.765 (1) A for (I) and (II), respectively.

2,2'-Dipyridyl↗
PubMed1991

Conformational comparison of 1,2-dimethyl-6-oxo-1,6-dihydro-3,4'-bipyridine-5-carbonitrile free base and its hydrobromide monohydrate salt.

C13H11N3O (I), Mr = 225.25, monoclinic, P21/c, a = 11.713 (4), b = 7.891 (3), c = 12.154 (4) A, beta = 92.27 (4) degrees, V = 1123 (1) A3, Z = 4, Dx = 1.333 Mg m-3, lambda (Mo K alpha) = 0.71073 A, mu = 0.082 mm-1, F(000) = 472, T = 293 K, R = 0.063 for 2579 reflections. 5-cyano-1,2-dimethyl-6-oxo-1,6-dihydro-3,4'-bipyridinium bromide monohydrate, C13H12N3O+.Br-.H2O (II), Mr = 324.18, orthorhombic, Pbca, a = 7.2893 (8), b = 18.955 (3), c = 19.814 (3) A, V = 2738 (1) A3, Z = 8, Dx = 1.573 Mg m-3, lambda (Mo K alpha) = 0.71073 A, mu = 2.972 mm-1, F(000) = 1312, T = 293 K, R = 0.086 for 2292 reflections. The twist angle around the bipyridine C(1)-C(1)' bond is 66.6 (2) and 44.1 (8) degrees for the free base (I) and its salt (II), respectively. The larger C(3)'-N(4)'-C(5)' pyridine ring angle [121.8 (5) degrees] in the salt structure compared with the corresponding value for the free base [116.1 (1) degrees] suggests that N(4)' is a protonation site. The water molecule in the salt structure (II) is disordered with occupancy refined to 0.6 and 0.4.

Cardiotonic Agents↗
PubMed1991

Computer graphic modeling in drug design--conformational analysis of antifolate binding to avian dihydrofolate reductase: crystal and molecular structures of 2,4-diamino-5-cyclohexyl-6-methylpyrimidine and 5-cyclohexyl-6-methyluracil.

The results of crystal structure determinations of the antifolate 2,4-diamino-5-cyclohexyl-6-methylprimidine (I), and its uracil derivative (II), show that the 5-cyclohexyl ring is gauche to the planar pyrimidine ring with torsion angles 82.4 (3) degrees and 63.7 (3) degrees for (I) and (II), respectively. Hydrogen bond patterns observed for these free base pyrimidines indicate a preference for N...N or N...O dimer formation around inversion centers, as observed in other antifolate structures. Computer graphic modeling studies were carried out comparing the avian dihydrofolate reductase active site interactions of the cyclohexyl antifolate (I) with the more potent 5-adamantyl analog and the less potent 5-hexyl and 5-heptyl antifolates. These data showed that although the cyclohexyl ring fits into the same conformational space as adamantyl, it makes fewer hydrophobic contacts. Similarly, cyclohexyl fills the active site better than either the 5-n-hexyl or heptyl side chains. These data are consistent with the increased potency of the adamantyl and cyclohexyl antifolates compared to n-alkyl analogs with similar hydrophobicities. These data indicate that the rigid structure of these ring systems increases their hydrophobic interactions, thus enhancing their biochemical activity.

Animals↗
PubMed1989

Interaction of amiodarone and its analogs with calmodulin.

Benzofurans have important actions on the electrical properties of myocardium; the biochemical basis of those actions is not known. Crystallographic examination of these compounds has revealed that benzofurans share structural homologies with the traditional calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene and trifluoperazine. In the present study, the ability of amiodarone, desethylamiodarone, and benziodarone to displace the fluorescent ligand 8-anilino-1-naphthalene sulfonic acid (ANS) from calmodulin, to modulate the fluorescence emission of dansylcalmodulin, and to inhibit the activation by calmodulin of bovine brain cyclic nucleotide phosphodiesterase and human erythrocyte membrane Ca2+-ATPase were investigated at concentrations ranging from 10(-8) to 10(-6) M. These benzofurans displaced ANS from calmodulin with nearly equal efficiency upon forming a 1:1 complex with that protein. Each of these compounds also produced a decreased fluorescence emission of dansylcalmodulin, but with relative efficiencies being desethylamiodarone greater than amiodarone greater than benziodarone. Amiodarone and desethylamiodarone inhibited calmodulin-stimulable phosphodiesterase activity with similar potencies. Amiodarone and benziodarone inhibited calmodulin-stimulable Ca2+-ATPase activity equally, but desethylamiodarone had no effect. The observed differential effects of the amiodarone analogs suggest that calmodulin may possess multiple benzofuran-binding sites that are recognized by specific targets and ligands of this Ca2+-binding protein and that the cellular action of amiodarone and its analogs may reflect calmodulin antagonism.

Amiodarone↗
PubMed1989

Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationships.

Protein kinase C (PKC) from rat brain was inhibited by plant flavonoids in a concentration-dependent manner depending on flavonoid structure. Of the fifteen flavonoids studied, fisetin, quercetin and luteolin were the most potent, while hesperetin, taxifolin and rutin were among the least potent. The flavonol fisetin was almost 100% inhibitory at a concentration of 100 microM. The extent of inhibition was the same whether diacylglycerol or 12-O-tetradecanoylphorbol-13-acetate was used as enzyme activator. Inhibition was independent of Ca2+, phospholipid, and enzyme activator, as shown by inhibition of protamine phosphorylation in the absence of the regulatory components. Fisetin was a competitive inhibitor with respect to ATP binding and noncompetitive with respect to protein substrate. The X-ray crystal structure analysis of hesperetin monohydrate showed that the molecule is essentially planar despite the sofa conformation of the gamma-pyran ring and the 27 degrees twist of the 2-phenyl ring. Comparison of this inactive flavanone with those of the active flavones showed that, although hesperetin can adopt a planar profile similar to those of fisetin and quercetin, the 4'-methoxy substituent blocks an essential structural feature required for inhibitory activity. Analysis of these structure-activity data revealed a model of the minimal essential features required for PKC inhibition by flavonoids: a coplanar flavone structure with free hydroxyl substituents at the 3', 4' and 7-positions.

Animals↗
PubMed1989

Structure of 1-amidino-3-(3-sulfamoylphenyl)urea hydrochloride.

1-(Diaminomethylene)-3-(3-sulfamoylphenyl)uronium chloride, C8H12N5O3S+.Cl, Mr = 293.71, monoclinic, P21/c, a = 10.148 (1), b = 7.881 (1), c = 15.286 (3) A, beta = 94.77 (1) degrees, V = 1218.2 A3, Z = 4, Dx = 1.601 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 4.838 cm-1, F(000) = 608, T = 294 K, R = 0.069 for 1779 data. The molecular conformation of the protonated arylamidinourea is completely planar and all amidinourea N atoms have considerable sp2 hybridization. The stable tautomeric form has an intramolecular hydrogen bond between the ureido O atom and an amidino N atom. All N atoms in the molecular packing make contact with the Cl- ion.

Crystallization↗
PubMed1989

Structure-activity relationships of antiarrhythmic agents: crystal structure of amiodarone hydrochloride and two derivatives, and their conformational comparison with thyroxine.

Amiodarone.HCl (I), 2-butyl-3-benzofuranyl 4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone hydrochloride, C25H30I2NO3+.Cl-, Mr = 680.78, monoclinic, P2(1)/c, a = 17.124 (2), b = 17.079 (2), c = 9.162 (1) A, beta = 98.37 degrees, V = 2651.2 A3, Z = 4, Dx = 1.71 g cm-3, lambda(Mo K alpha) = 0.7107 A, mu = 24.73 cm-1, F(000) = 1332, T = 294 K, R = 6.6% for 5515 data; desethyl-amiodarone.HCl (II), 2-butyl-3-benzofuranyl 4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl ketone hydrochloride, C23H26I2NO3+.Cl-, Mr = 654.74, monoclonic, P2(1)/c, a = 23.867 (2), b = 10.134 (1), c = 10.287 (2) A, beta = 93.91 (2) degrees, V = 2482.5 A3, Z = 4, Dx = 1.75 g cm-3, lambda(Mo K alpha) = 0.07107 A, mu = 26.37 cm-1, F(000) = 1276, T = 294 K, R = 5.7% for 5916 data; benziodarone (III), 2-ethyl-3-benzofuranyl 4-hydroxy-3,5-diiodophenyl ketone, C17H12I2O3, Mr = 518.09, monoclinic, P2(1)/n, a = 17.564 (2), b = 8.294 (1), c = 11.587 (2) A, beta = 93.20 (2) degrees, V = 1685.55 A3, Z = 4, Dx = 2.04 g cm-3, lambda(Mo K alpha) = 0.7101 A, mu = 36.99 cm-1, F(000) = 976, T = 294 K, R = 6.2% for 4311 data.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1988

Thyroid hormone structure-activity relationships: molecular structure of 3,5,3'-triiodothyropropionic acid.

The crystal and molecular structures of 3,5,3'-triiodothyropropionic acid (T3P), determined as an N-diethanolamine salt, were carried out and the results are compared with those of other thyroid hormone structures. These data show that T3P has an unusual conformation with the diphenyl ether bridge outside the range normally observed for other thyroactive acid structures and has the largest deviations from the ideal skewed conformation predicted for 3,5-diiodothyroactive compounds. These conformational properties are not observed in the structures of thyroformic or acetic acid analogues. Biochemical data indicate that thyropropionic acid analogue activity differs from that other acid analogues which could imply that their metabolism and activity can be controlled differently from that of other hormone metabolites.

Crystallography↗
PubMed1988

Crystal and molecular structures of flavonoids.

Flavonoids are a broadly distributed class of plant pigments, universally present in vascular plants and responsible for much of the coloring in nature. Because of their widespread occurrence in edible plants, flavonoids are an integral part of the human diet. Therefore, the effects of these substances on human nutrition and well-being are of considerable importance, in particular in cultures where they constitute a major portion of the diet. To understand their mechanisms of action in various cellular and enzyme systems, it is important to have knowledge of their molecular properties. Structural studies have shown the three-dimensional conformations of these natural plant products, delineating their conformational preferences, showing the influence of substituents on conformation and physical properties. The results of these studies show that a single flavonoid may have more than one response, depending on enzyme site. Analysis of these flavonoid structure-activity relationships has offered insight into their mechanisms of action and will be instrumental in the design of new drugs based on these natural products. Thus, their diverse effects endow the flavonoids with an immense capacity to contribute important new therapeutic agents for the treatment of disease.

Crystallography↗
PubMed1987

Competition of milrinone, a non-iodinated cardiac inotropic agent, with thyroid hormone for binding sites on human serum prealbumin (TBPA).

Milrinone [2-methyl-5-cyano-(3,4'-bipyridin)-6(1H)-one] is a positive cardiac inotropic agent recently shown to have thyromimetic activity in vitro in a rabbit myocardial membrane Ca2+-ATPase system [K. M. Mylotte et al., Proc. natn. Acad. Sci. U.S.A. 82, 7974 (1985)]. In the present studies, milrinone was examined for activity as an inhibitor of iodothyronine binding by human serum thyroid hormone transport proteins, thyroxine-binding globulin (TBG), prealbumin (TBPA) and albumin. Polyacrylamide gel electrophoresis at pH 9.0 of sera equilibrated with [125I]thyroxine showed that milrinone competed with L-thyroxine (T4) for binding sites on TBPA (10 and 100 microM milrinone caused 61 and 73% reductions, respectively, in T4 binding to TBPA, P less than 0.01); T4 displaced from TBPA was bound by TBG and albumin. Comparable reductions in T4 binding to TBPA were observed in electrophoretic studies conducted at pH 7.4. Binding of triiodo-L-thyronine (T3) to TBPA was electrophoretically confirmed and shown to be decreased in the presence of milrinone. Electrophoresis of purified TBPA also demonstrated that [14C]milrinone co-migrated with this transport protein and that milrinone displaced tracer T4 from TBPA. Amrinone, the 2-H-5-NH2 analog of milrinone, had less than 5% of the activity of milrinone as an inhibitor of T4 binding in electrophoretic studies. Scatchard analysis of T4 and milrinone binding to purified TBPA, measured by equilibrium dialysis, showed two classes of binding sites, with association constants, respectively, of 6.1 X 10(7) M-1 and 1.6 X 10(6) M-1 for T4, and 1.7 X 10(6) M-1 and 8.9 X 10(2) M-1 for milrinone. Computer graphic modeling of the binding of milrinone to the T4 site in the crystal structure of TBPA showed that milrinone best occupied this site when the substituted bipyridine ring overlapped the phenolic ring of T4. In this orientation the 5-cyano group, which has an electronegativity similar to that of iodine, occupied the same volume as the 5'-iodine of T4. The 5-amino group of amrinone lacks these characteristics. In this orientation, the keto function of milrinone overlapped the T4 4'-hydroxyl and could participate in similar intermolecular interactions. Thus, milrinone, a non-iodinated bipyridine, and thyroid hormone share structural and biochemical homologies and compete for the same binding site on TBPA.

Amrinone↗