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PubMed1973

Altered enzymes in drug-resistant variants of mammalian tissue culture cells.

Two selective procedures are compared in an effort to isolate variants of mouse L cells containing structural gene mutations. Among the resulting variant cloned cell lines are found two types of alterations in the enzyme hypoxanthine phosphoribosyl transferase (EC 2.4.2.8) (1): enzyme with altered kinetic constants causing in vivo and in vitro resistance to 8-azaguanine; and (2) enzyme with altered heat sensitivity in vitro. These results support the view that tissue culture cell variants can arise from structural gene mutations.

Animals↗
PubMed1980

Endocrine differentiation in mucoid carcinoma of the breast.

Mucoid carcinoma of the breast is not a single homogeneous entity. It comprises two main variants separable on structural and cytological grounds and a smaller transitional type. The salient pathological differences are detailed. One variant is usually arygrophilic and contains dense core granules of the type seen in endocrine tumours. Both endocrine and amphicrine cells have been identified in this sub-type. The relationship of this endocrine variant of mucoid carcinoma to other argryophil carcinomas (so-called 'carcinoids') of the breast is discussed.

Adenocarcinoma, Mucinous↗
PubMed1975

Cytogenetic evaluation of 500 Jerusalem newborn infants.

Cytogenetic investigations were carried out on cord blood lymphocytes of 500 normal healthy newborns. This population was divided into seven geoethnic groups according to the birthplace of the four grandparents of the infant. No numerical chromosomal aberrations were observed, but 10% of the individuals manifested cytogenetic variants. Six inherited structural abnormalities (four inversions and two deletions) were observed, while the remainder were classified as "minor variants." The chromosomal variants were randomly distributed among the population, and no particular variant was characteristic of a given subgroup.

Cells, Cultured↗
PubMed2004

Stereochemistry of insect kinin tetrazole analogues and their diuretic activity in crickets.

Insect kinin analogues of the sequence Phe-Phe-psi[CN(4)]-Ala-Trp-Gly-NH(2) containing (L-Phe(2),L-Ala(3)) and (L-Phe(2),D-Ala(3)) stereochemical variants of the tetrazole moiety, a mimic of the type VI beta-turn, demonstrate significant agonist and partial antagonist activity, respectively, in a cricket diuretic bioassay. A comparison of the solution conformations of these two stereochemical variants indicates a structural basis for their divergent bioactivities. The (D-Phe(2),D-Ala(3)) stereochemical variant was synthesized and found to demonstrate significant agonist activity. The results further define stereochemical requirements for the diuretic activity of insect kinins in crickets and provide valuable information for the design of biostable analogues capable of disrupting digestive and diuretic processes in pest insects.

Amino Acid Sequence↗
PubMed1988

Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: a structure-activity study.

Combretastatin, an antineoplastic and antimitotic agent, was isolated from the bark of Combretum caffrum [Can. J. Chem. 60: 1374-1376 (1982); Biochem. Pharmacol. 32:3864-3867 (1983)]. Structurally, combretastatin consists of two substituted benzene rings linked by a saturated, hydroxy-substituted two-carbon bridge. A large number of combretastatin analogs have now been synthesized or obtained from C. caffrum. These vary in substituents on the phenyl rings or bridge carbons, bridge length, unsaturation of the bridge (i.e., stilbene derivatives, with the two phenyl rings oriented either cis or trans), and in precise ring structure (two major variants, with the bridge incorporated into a third six-member ring to form a phenanthrene structure or a methyl group eliminated from vicinal methoxy substituents to form a benzodioxole ring). Available analogs (17 natural products and 22 synthetic agents) were examined for antimitotic and cytotoxic activity and for effects on tubulin polymerization and colchicine binding. Nineteen compounds inhibited cell growth by 50% or more at concentrations of 1 microM or less, and 14 inhibited tubulin polymerization by at least 50% at stoichiometric drug concentrations. The most potent cytotoxic agents generally strongly inhibited both tubulin polymerization and the binding of colchicine to tubulin. The most promising compound is the (cis)-stilbene derivative (cis)-1-(3,4,5-trimethoxyphenyl)-2-(3'-hydroxy-4'-methoxyphenyl)ethene, which has been named combretastatin A-4. This compound inhibited cell growth by 50% at 7 nM, inhibited tubulin polymerization by 50% at 2.5 microM (1/4 molar equivalent), and competitively inhibited colchicine binding with an apparent Ki of 0.14 microM.

Animals↗
PubMed1981

[Ultrastructure of the polysome-lamella complexes in ovarian cancers].

Electron-microscopy was used to study the intraoperative material in 37 patients with serous (24), mucinous (8) and endometroid (5) ovarian neoplasms of benign, boundary and malignant forms. It was shown that the polysome-lamellae complexes are characteristic only of the carcinoma epithelium and practically are observed neither in benign nor in boundary analogs. This may serve an additional criterion of a malignant nature of neoplasms at the ultrastructural level. Taking into account the architectonics 3 variants of the polysome-lamellae complexes should be distinguished: polysome-lamellae, lamellae and lattice structures. All these variants may be encountered in one and the same tumor.

Adenocarcinoma↗
PubMed2002

Crystal structures and increased stabilization of the protein G variants with switched folding pathways NuG1 and NuG2.

We recently described two protein G variants (NuG1 and NuG2) with redesigned first hairpins that were almost twice as stable, folded 100-fold faster, and had a switched folding mechanism relative to the wild-type protein. To test the structural accuracy of our design algorithm and to provide insights to the dramatic changes in the kinetics and thermodynamics of folding, we have now determined the crystal structures of NuG1 and NuG2 to 1.8 A and 1.85 A, respectively. We find that they adopt hairpin structures that are closer to the computational models than to wild-type protein G; the RMSD of the NuG1 hairpin to the design model and the wild-type structure are 1.7 A and 5.1 A, respectively. The crystallographic B factor in the redesigned first hairpin of NuG1 is systematically higher than the second hairpin, suggesting that the redesigned region is somewhat less rigid. A second round of structure-based design yielded new variants of NuG1 and NuG2, which are further stabilized by 0.5 kcal/mole and 0.9 kcal/mole.

Crystallography, X-Ray↗
PubMed1969

Internal and surface structure of Hong Kong influenza virus.

Negative-contrast electron-microscope studies of the A2/Aichi/2/68 strain of the Hong Kong influenza virus variant have revealed structural details which are compared with those of other influenza viruses.The structures of the ribonucleoprotein strand and of the virus envelope, in particular, are illustrated at magnifications of from x200 000 to x330 000.The authors conclude that by the microscope technique used the Hong Kong virus is indistinguishable from earlier influenza A viruses and similar in general design to influenza C viruses.

Microscopy, Electron↗
PubMed2002

R-Ras glucosylation and transient RhoA activation determine the cytopathic effect produced by toxin B variants from toxin A-negative strains of Clostridium difficile.

Clostridium difficile induces antibiotic-associated diarrhea through the production of toxin A and toxin B; the former toxin has been assumed to be responsible for the symptoms of the disease. Several toxin A-negative strains from C. difficile have recently been isolated from clinical cases and have been reported to produce toxin B variants eliciting an atypical cytopathic effect. Ultrastructural analysis indicated these toxins induce a rounding cytopathic effect and filopodia-like structures. Toxin B variants glucosylated R-Ras, and transfection with a constitutively active mutant of this GTPase protected cells against their cytopathic effect. Treatment of cells with toxin B variants induced detachment from the extracellular matrix and blockade of the epidermal growth factor-mediated phosphorylation of extracellular-regulated protein kinases, demonstrating a deleterious effect on the R-Ras-controlled avidity of integrins. Treatment with toxin B variants also induced a transient activation of RhoA probably because of inactivation of Rac1. Altogether, these data indicate that the cytopathic effect induced by toxin B variants is because of cell rounding and detachment mediated by R-Ras glucosylation, and the induction of filopodia-like structures is mediated by RhoA activation. Implications for the pathophysiology of C. difficile-induced diarrhea are discussed.

3T3 Cells↗
PubMed1995

Modelling the three-dimensional structure and the electrostatic potential field of two Cu,Zn superoxide dismutase variants from tomato leaves.

The three-dimensional structure of tomato P31 and T10 Cu,Zn superoxide dismutases (SODs) were computer modelled using the structure of the bovine enzyme as a template. The structure-essential residues retain in the models the position occupied in the other Cu,Zn SODs of known 3D structure and the overall packing of the beta-barrel is maintained. Formation of 'aromatic pairs' occurs between newly inserted aromatic residues. The number of total charges changes in the two variants and some charged residues located in the proximity of the active site in most Cu,Zn SODs disappear in tomato enzymes. Calculation of the electrostatic potential field, carried out by numerically solving the Poisson-Boltzmann equation, indicates that in both variants a negative potential field surrounds all the protein surface except the active site areas, characterized by positive potential values, as already observed in the bovine enzyme. This result confirms that coordinated mutations of charged residues have occurred in the evolution of this enzyme giving rise to a peculiar electrostatic potential distribution common to all members of this protein family.

Amino Acid Sequence↗
PubMed1996

Dynamic simulations of the molecular conformations of wild type and mutant xanthan polymers suggest that conformational differences may contribute to observed differences in viscosity.

Xanthan gum is an exopolysaccharide secreted by the bacterium Xanthamonas campestris whose ability to make solutions viscous at low concentrations and over a pH and temperature range have generated much interest in both academic and industrial environments. Mutant Xanthamonas strains have been derived that produce xanthan gums with an altered or variant subunit chemical structure and different measured viscosities when compared with the wild type (wt) form of the polymer. Two variant gums were targeted as potentially interesting in this study, these being the nonacetylated tetramer (natet) and the acetylated tetramer (atet), which both lack a side-chain terminal mannose residue and in one case (natet) lacks an acetate group on an internal mannose residue. Solutions of these tetrameric gums possess viscosities higher (natet) and lower (atet) than the wt gum, and therefore we have attempted to determine whether these molecules possess unique conformational preferences when compared with the wt and with each other. In this manner we can initiate an understanding of how a polysaccharide's conformation contributes to its solution properties. The GEGOP software permits a sampling of the static and dynamic equilibrium states of carbohydrate molecules, and this software was employed to calculate equilibrium states of representative oligosaccharides with chemical structures representative of xanthan-like molecules. Energy minimization techniques revealed similar local minima for all three molecules. Some of these minima are comprised of elongate backbone conformations (A type) in which side chains fold onto backbone surfaces. Other minima with A backbones possessed side chains in less intimate backbone contact especially when calculations were performed with a low dielectric constant. This phenomenon was particularly pronounced in the wt molecule where an increased number of negatively charged side-chain residues experience charge repulsion resulting in reduced side-chain-backbone contact. Metropolis Monte Carlo (MMC) dynamic simulations performed with an elevated temperature factor (1000 K) allowed a better qualitative representation of conformational space than 300 K simulations. Employing a nonhierarchical cluster analysis method (population density profile: PDP) coupled with a classification scheme, it was possible to partition resulting MMC data sets into conformational families. This analysis revealed that in simulations performed with different dielectric constant values (10, 25, and infinity) all molecules possessed primarily A-type backbones. Less elongate, more open helical backbone forms (B, C, D, J, and Flat-a) did occur during the simulations but were populated to a lesser extent. In the natet molecule significantly open helical backbones existed (E, F, G, H, and I) that did not occur in the lower viscosity wt and atet molecules. PDP clustering methods and subsequent conformational classification applied to the first residue (mannose) of the side chain permitted a determination of side-chain orientation. Comparison of all three molecules indicated a larger population of side-chain conformational families in less direct backbone contact for the wt molecule than either of the variant molecules (natet/atet) suggesting that the side chains in the wt are more flexible. Thus, a major conformational difference between the high viscosity natet and the lower viscosities of the wt/atet is the increased amount of open helical backbone in the natet. In addition, the significant difference between the higher viscosity wt and the lower viscosity atet is the increase side-chain flexibility in the wt. We hypothesize that conformational differences of this kind could form a partial explanation of the observed differences in viscosity between these xanthan-like polymers.

Carbohydrate Conformation↗
PubMed1995

The role of a conserved tyrosine residue in high-potential iron sulfur proteins.

Conserved tyrosine-12 of Ectothiorhodospira halophila high-potential iron sulphur protein (HiPIP) iso-I was substituted with phenylalanine (Y12F), histidine (Y12H), tryptophan (Y12W), isoleucine (Y12I), and alanine (Y12A). Variants Y12A and Y12I were expressed to reasonable levels in cells grown at lower temperatures, but decomposed during purification. Variants Y12F, Y12H, and Y12W were substantially destabilized with respect to the recombinant wild-type HiPIP (rcWT) as determined by differential scanning calorimetry over a pH range of 7.0-11.0. Characterization of the Y12F variant by NMR indicates that the principal structural differences between this variant and the rcWT HiPIP result from the loss of the two hydrogen bonds of the Tyr-12 hydroxyl group with Asn-14 O delta 1 and Lys-59 NH, respectively. The effect of the loss of the latter interaction is propagated through the Lys-59/Val-58 peptide bond, thereby perturbing Gly-46. The delta delta GDapp of Y12F of 2.3 kcal/mol with respect to rcWT HiPIP (25 degrees C, pH 7.0) is entirely consistent with the contribution of these two hydrogen bonds to the stability of the latter. CD measurements show that Tyr-12 influences several electronic transitions within the cluster. The midpoint reduction potentials of variants Y12F, Y12H, and Y12W were 17, 19, and 22 mV (20 mM MOPS, 0.2 M sodium chloride, pH 6.98, 25 degrees C), respectively, higher than that of rcWT HiPIP. The current results indicate that, although conserved Tyr-12 modulates the properties of the cluster, its principle function is to stabilize the HiPIP through hydrogen bonds involving its hydroxyl group and electrostatic interactions involving its aromatic ring.

Bacteria↗
PubMed2000

Genetic variation in the B7-1 gene in patients with multiple sclerosis.

Co-stimulation of T cells by B7-1, a protein that is expressed on antigen presenting cells, favors a T helper type1 (Th1) cellular response. Th1/Th2 bias may influence disease susceptibility or course of MS. We screened the entire coding sequence as well as the 5'- and 3'-untranslated regions of the B7-1 gene using a mutation scanning technique, dideoxyfingerprinting, in DNA from 111 patients with MS from Olmsted County, Minnesota. We identified five genetic variants. None alter protein structure nor have apparent functional significance. Selected variants of sufficient frequency were tested for an association with course and severity of MS and one was tested for an association with susceptibility; none of the association tests were positive.

3' Untranslated Regions↗
PubMed1991

Alternative modes of self-cleavage by newt satellite 2 transcripts.

Synthetic transcripts of satellite 2 DNA from the newt undergo self-catalyzed cleavage in vitro. In this report we present evidence that there are at least two distinct modes of satellite 2 transcript self-cleavage. In one mode, a single cleavage domain folds into a structure which cleaves at a slow rate. This structure may be analogous to, or a variant of, the 'hammerhead' structure believed to be active during the self-cleavage of a number of infectious plant RNAs. In an alternative mode, multiple cleavage domains interact to cleave at an enhanced rate. The permutation of the repeated satellite 2 sequence determines which of these modes of cleavage will predominate, presumably by influencing the overall conformation of the RNA. We present a model for the self-processing of multimeric satellite 2 transcripts which incorporates both of these modes of self-cleavage.

Animals↗
PubMed2004

Heavy fermion superconductivity and magnetic order in noncentrosymmetric CePt3Si.

CePt3Si is a novel heavy fermion superconductor, crystallizing in the CePt3B structure as a tetragonally distorted low symmetry variant of the AuCu3 structure type. CePt3Si exhibits antiferromagnetic order at T(N) approximately 2.2 K and enters into a heavy fermion superconducting state at T(c) approximately 0.75 K. Large values of H(')(c2) approximately -8.5 T/K and H(c2)(0) approximately 5 T refer to heavy quasiparticles forming Cooper pairs. Hitherto, CePt3Si is the first heavy fermion superconductor without a center of symmetry.

Journal Article↗
PubMed1986

[Characteristics of the course of cyclothymia-like schizophrenia in puberty].

Slowly progressive schizophrenia with subclinical affective attacks in adolescence is characterized by undoubtful differences in the premorbid characteristics of patients, clinical picture and peculiarities of the course of the endogenic process. Different variants of the course are related to structurally and phenomenologically different variants of affective attacks. The more similar is the course of cyclothymia-like schizophrenia to protracted non-remission one, the more atypical are affective attacks (adynamic depressions and nonproductive hypomania); the more paroxysmal is the course, the more marked and diverse is the clinical picture of depression (dysphoric attacks) and the more typical are hypomanias. Patients with cyclothymia-like schizophrenia, besides therapy, are in need of the earliest possible rehabilitative treatment aimed at the continuation of education under easier conditions which expedites post-attack readaptation and improves social prognosis.

Adolescent↗
PubMed1994

Structural characterization of heme ligation in the His64-->Tyr variant of myoglobin.

A site-specific mutant of horse heart myoglobin has been prepared in which the distal heme pocket residue, His64, is replaced by tyrosine. The structure of this myoglobin variant has been determined to 2.0-A resolution using x-ray diffraction techniques and refined to a final crystallographic R-factor of 16.9%. The polypeptide backbone conformation of the His64-->Tyr variant of myoglobin is very similar to that of the wild-type protein. However, in the variant the water normally found coordinated to the heme iron atom and hydrogen-bonded to His64 has been displaced by the hydroxyl oxygen of the Tyr64 side chain. The tyrosine oxygen atom is directly coordinated to the heme iron atom with a bond length of 2.18 A. Distortion of heme planarity and changes in the packing of the Leu29 and Leu104 side chains are related to this mutation. The ligand environment of the ferric iron has been studied by electron paramagnetic resonance (EPR) spectroscopy using crystalline material and protein in solution. The protein in solution exhibits a rhombically split ferric high spin EPR spectrum with g values of 6.64, 5.34, and 1.98. The EPR spectrum of the crystalline sample consists of two different ferric high spin signals. The main signal is similar to the signal observed in solution and is assigned to His93-Fe(III)-Tyr64 coordination. The relatively high rhombicity of this signal can be explained as arising from distortions of the heme plane seen in the crystal structure. The second, more axial high spin signal found in the crystalline state can be tentatively assigned to another form of iron ligation with a different iron-tyrosine bond length and a less distorted heme plane.

Animals↗
PubMed2000

Toward a high-resolution structure of phospholamban: design of soluble transmembrane domain mutants.

Determination of a high-resolution structure of the phospholamban (PLB) transmembrane domain by X-ray crystallography or NMR is handicapped by the hydrophobic nature of the peptide. Interestingly, the crystal structure of the five-stranded parallel coiled-coil oligomerization domain from cartilage oligomeric matrix protein (COMPcc) shows marked similarities to a model proposed for the pentameric transmembrane domain of PLB. Contrary to the putative coiled-coil domain of PLB, COMPcc contains mostly hydrophilic amino acids on the surface, resulting in a soluble molecule. Here, we report the design of soluble PLB transmembrane domain variants by combining the surface residues of COMPcc and the hydrophobic interior of the transmembrane domain of PLB. The soluble PLB variants formed pentameric structures as revealed by analytical ultracentrifugation. After redox shuffling, they showed unspecific disulfide bridge patterns similar to that of the chemically synthesized wild-type PLB transmembrane domain. These results suggest a structural homology between the soluble PLB mutants and the wild-type PLB transmembrane domain. Together with the data reported in the literature, they furthermore indicate that residues Leu37, Ile40, Leu44, and Ile47 of the PLB sequence specify pentamer formation. In contrast, a designed recombinant COMPcc mutant, COMP-ARCC, which was engineered to contain the two PLB cysteines that potentially could form an interchain disulfide bridge, formed a specific disulfide bond pattern. This finding indicates structural differences between the transmembrane domain of PLB and COMPcc. The soluble PLB variants may be used to determine a high-resolution structure of the PLB pentamer by X-ray crystallography.

Amino Acid Sequence↗