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PubMed1995

Structural variation of novel alleles at the Hum vWA and Hum FES/FPS short tandem repeat loci.

This paper reports the sequences of novel alleles identified during population databasing studies on the short tandem repeat loci HumvWA and HumFES/FPS. Two HumFES/FPS alleles follow the simple repeat pattern (ATTT)7 and (ATTT)15. Sequence variation corresponding to an A to C transversion occurred in the 5' flanking region in two individuals possessing the designated allele 7. Two HumvWA alleles exhibited compound repeat regions comprising TCTA and TCTG repeat units. Sequence analysis confirmed the putative designation of 11 for a 127 base pair allele. However, a 131 base pair allele, putatively designated as 12, exhibited a more complex sequence. Two different types of repeat unit structures were identified which also exhibited sequence variation in the 3' flanking region.

Alleles↗
PubMed1983

Antigenic and structural variations in the cholera/coli family of enterotoxins.

Recent observations establish the existence of a family of ADP-ribosylating, adenylate cyclase-activating, heat-labile enterotoxins which are structurally, functionally, and immunologically related to the cholera enterotoxin. Despite their overall similarity, it is clear that there are significant structural and immunological differences within the group. These conclusions are supported by extensive experiments comparing the precipitin activity and neutralizing effects of various specific antisera, before and after purification by immunoaffinity chromatography and solid phase immunoaffinity adsorption of common and cross-reactive antibody species, on the various pure enterotoxins. It will be of great importance to determine the full range of the antigenic and structural drift among this family of enterotoxins. The results will have significance in efforts to develop effective broad spectrum antitoxic immunity and also in the development of rapid and reliable techniques for the identifications of enterotoxic enteropathogens.

Antigens, Bacterial↗
PubMed2001

Structural variations and bonding in gold halides: a quantum chemical study of monomeric and dimeric gold monohalide and gold trihalide molecules, AuX, Au2X2, AuX3, and Au2X6 (X = F, Cl, Br, I).

The molecular structures of all gold mono- and trihalides and of their dimers have been calculated at the B3LYP, MP2, and CCSD(T) levels of theory by using relativistic pseudopotentials for all atoms except fluorine. Our computations support the experimental observation that the relative stability of the monohalides increases from the fluoride toward the iodide, while the stability trend of the trihalides is the opposite. The potential energy surface (PES) of all gold trihalides has been investigated. These molecules are typical Jahn-Teller systems; the trigonal planar D3h-symmetry geometry does not correspond to the minimum energy structure for any of them. At the same time, the amount and character of their Jahn-Teller distortion changes gradually from AuF3 to AuI3. The minimum energy geometry is a T-shaped structure for AuF3 and AuCl3, with a Y-shaped transition-state structure. For AuI3, the Y-shaped structure lies lower than the T-shaped structure on the PES. For AuBr3 and AuI3, neither of them is the global minimum but instead an L-shaped structure, which lies outside the Jahn-Teller PES. This structure can be considered to be a donor-acceptor system, or a closed-shell interaction, with I2 acting as donor and AuI as acceptor. The dimers of gold monohalides have very short gold-gold distances and demonstrate the aurophilic interaction. The dimers of the trihalides are planar molecules with two bridging halogen atoms.

Journal Article↗
PubMedDate not supplied

Phenotypic effects of apolipoprotein structural variation on lipid profiles. III. Contribution of apolipoprotein E phenotype to prediction of total cholesterol, apolipoprotein B, and low density lipoprotein cholesterol in the healthy women study.

The apolipoprotein (apo) E structural locus has been shown to influence concentrations of total cholesterol, apo B, and low density lipoprotein (LDL) cholesterol in population studies. Apo E has six phenotypes resulting from three common alleles at this locus. In the present study, we have typed 473 healthy white women for apo E. At baseline in 1984, all women were premenopausal. To date, 109 of these women have become postmenopausal and are not on hormone therapy. Statistical analyses were done on both pre- and postmenopausal groups to assess the influence of menopausal status in combination with the apo E locus on lipid profile. Nine lipoprotein lipids and apolipoproteins were categorized by three apo E phenotypes: apo E3-2, apo E3-3, and apo E4-3. These were compared in analysis of variance. At baseline, the apo E3-2 phenotype showed the lowest average concentrations of total cholesterol (170 mg/dl), apo B (80 mg/dl), and LDL cholesterol (91 mg/dl), while the apo E4-3 phenotype demonstrated the highest average concentrations of total cholesterol (192 mg/dl), apo B (104 mg/dl), and LDL cholesterol (116 mg/dl) (p less than or equal to 0.0004). Apo E3-3 homozygotes were intermediate on all three quantitative variables. The postmenopausal subset showed the same trends by phenotype, with overall increases in total cholesterol, apo B, LDL cholesterol, and triglycerides, regardless of phenotype. Women who remained premenopausal generally showed smaller increases in these same measures. Our results suggest that, on average, the lower lipoprotein values for the apo E3-2 phenotype are maintained through early menopause despite a worsening of lipid profiles for all women as they age.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1985

The predicted presence of large helical structural variation in yeast HIS4 upstream region is correlated with general amino acid control on the CYC1 gene.

A series of CYC1 constructions in which the upstream promoter portion has been replaced by a variety of HIS4 synthetic fragments has demonstrated that the 5' TGACTC 3' repeat is crucial for conferring amino acid general control. Efficient regulation, however, is obtained only with fragments containing both the repeat and flanking sequences. Analysis of the flanks shows the presence of a 16 nucleotide long sequence composed of alterations of two purines and two pyrimidines between the upstream and downstream repeats. Such a sequence has very large twist angle variations. Homologous sequence are observed in HIS1, HIS3, and in TRP5 upstream regions between copies of the repeat. Sequences which confer special structural characteristics may aid in protein recognition of the promoter region.

Amino Acids↗
PubMed2000

Genetic influence on the structural variations of the abnormal prion protein.

Prion diseases are characterized by the presence of the abnormal prion protein PrP(Sc), which is believed to be generated by the conversion of the alpha-helical structure that predominates in the normal PrP isoform into a beta-sheet structure resistant to proteinase K (PK). In human prion diseases, two major types of PrP(Sc), type 1 and 2, can be distinguished based on the difference in electrophoretic migration of the PK-resistant core fragment. In this study, protein sequencing was used to identify the PK cleavage sites of PrP(Sc) in 36 cases of prion diseases. We demonstrated two primary cleavage sites at residue 82 and residue 97 for type 1 and type 2 PrP(Sc), respectively, and numerous secondary cleavages distributed along the region spanning residues 74-102. Accordingly, we identify three regions in PrP(Sc): one N-terminal (residues 23-73) that is invariably PK-sensitive, one C-terminal (residues 103-231) that is invariably PK-resistant, and a third variable region (residues 74-102) where the site of the PK cleavage, likely reflecting the extent of the beta-sheet structure, varies mostly as a function of the PrP genotype at codon 129.

Brain Chemistry↗
PubMed1996

The relationship between structural variation and dysgenic properties of P elements in long-established P-transformed lines of Drosophila simulans.

Ten lines of Drosophila simulans were investigated with respect to P activity, P susceptibility and the number and structure of their P copies, eight years after transformation with the P element. All 10 were found to have reached a steady state. They exhibited varying levels of P activity (from 0 per cent to 96 per cent GD sterility) and, with the exception of one line, were not P-susceptible. In contrast with P element behaviour in D. melanogaster: (i) no relationship was found between the molecular pattern of P copies in a line and its ability to induce or to repress P expression in D. simulans; (ii) peculiar P element derivatives were observed in this species; (iii) the average number of P copies per genome was only half of that in D. melanogaster. This may result from transposon-host genome interactions, which lead to a low invading power of the P element in D. simulans.

Animals↗
PubMed1992

Alkylphosphocholines: influence of structural variation on biodistribution at antineoplastically active concentrations.

Hexadecylphosphocholine (HPC) and octadecylphosphocholine (OPC) show very potent antitumor activity against autochthonous methylnitrosourea-induced mammary carcinomas in rats. The longer-chain and unsaturated homologue erucylphosphocholine (EPC) forms lamellar structures rather than micelles, but nonetheless exhibits antineoplastic activity. Methylnitrosourea was used in the present study to induce autochthonous mammary carcinomas in virgin Sprague-Dawley rats. At 6 and 11 days following oral therapy, the biodistribution of HPC, OPC and EPC was analyzed in the serum, tumor, liver, kidney, lung, small intestine, brain and spleen of rats by high-performance thin-layer chromatography. In contrast to the almost identical tumor response noted, the distribution of the three homologues differed markedly. The serum levels of 50 nmol/ml obtained for OPC and EPC were much lower than the value of 120 nmol/ml measured for HPC. Nevertheless, the quite different serum levels resulted in similar tumor concentrations of about 200 nmol/g for all three of the compounds. Whereas HPC preferably accumulated in the kidney (1 mumol/g), OPC was found at increased concentrations (400 nmol/g) in the spleen, kidney and lung. In spite of the high daily dose of 120 mumol/kg EPC as compared with 51 mumol/kg HPC or OPC, EPC concentrations (100-200 nmol/g) were low in most tissues. High EPC concentrations were found in the small intestine (628 nmol/g). Values of 170 nmol/g were found for HPC and OPC in the brain, whereas the EPC concentration was 120 nmol/g. Obviously, structural modifications in the alkyl chain strongly influence the distribution pattern of alkylphosphocholines in animals. Since EPC yielded the highest tissue-to-serum concentration ratio in tumor tissue (5.1) and the lowest levels in other organs, we conclude that EPC is the most promising candidate for drug development in cancer therapy.

Animals↗
PubMed2001

The biological effects of structural variation at the meta position of the aromatic rings and at the end of the alkenyl chain in the alkenyldiarylmethane series of non-nucleoside reverse transcriptase inhibitors.

In an effort to elucidate a set of structure-activity relationships in the alkenyldiarylmethane (ADAM) series of non-nucleoside reverse transcriptase inhibitors, a number of modifications were made at two locations: (1) the meta positions of the two aromatic rings and (2) the end of the alkenyl chain. Forty-two new ADAMs were synthesized and evaluated for inhibition of the cytopathic effect of HIV-1(RF) in CEM-SS cell culture and for inhibition of HIV-1 reverse transcriptase. The size of the aromatic substituents was found to affect anti-HIV activity, with optimal activity appearing with Cl, CH(3), and Br substituents and with diminished activity occurring with smaller (H and F) or larger (I and CF(3)) substituents. The substituents at the end of the alkenyl chain were also found to influence the antiviral activity, with maximal activity associated with methyl or ethyl ester groups and with diminished activity resulting from substitution with higher esters, amides, sulfides, sulfoxides, sulfones, thioesters, acetals, ketones, carbamates, ureas, and thioureas. Twelve of the new ADAMs displayed submicromolar EC(50) values for inhibition of the cytopathic effect of HIV-1(RF) in CEM-SS cells. Selected ADAMs, 19 and 21, were compared to previously published ADAMs 15 and 17 for antiviral efficacy and activity against the HIV-1 reverse transcriptase enzyme. All four ADAMs were found to inhibit HIV-1 reverse transcriptase enzyme activity, to inhibit the replication of a variety of HIV-1 clinical isolates representing syncytium-inducing, nonsyncytium-inducing, and subtype representative isolates, and to inhibit HIV-1 replication in monocytes. Subsequent assessment against a panel of site-directed reverse transcriptase mutants in NL4-3 demonstrated no effect of the K103N mutation on antiviral efficacy and a slight enhancement (6- to 11-fold) in sensitivity to AZT-resistant viruses. Additionally, ADAMs 19 (44-fold) and 21 (29-fold) were more effective against the A98G mutation (found in association with nevirapine resistance in vitro), and ADAM 21 was 5-fold and 2-fold more potent against the Y181C inactivation mutation than the previously reported ADAMs 15 and 17, respectively. All four ADAMs were tested for efficacy against a multidrug-resistant virus derived from a highly experienced patient expressing resistance to the reverse transcriptase enzyme inhibitors AZT, ddI, 3TC, d4T, foscarnet, and nevirapine, as well as the protease inhibitors indinavir, saquinavir, and nelfinavir. ADAM 21 was 2-fold more potent than ADAM 15 and 6-fold more potent than ADAMs 17 and 19 at preventing virus replication. Thus, we have identified a novel series of reverse transcriptase inhibitors with a favorable profile of antiviral activity against the primary mutation involved in clinical failure of non-nucleoside reverse transcriptase inhibitors, K103N, and that retain activity against a multidrug-resistant virus.

Alkenes↗
PubMed1986

Structural variation in mammalian gamma-crystallins based on computer graphics analyses of human, rat and calf sequences. 1. Core packing and surface properties.

A comparison of mammalian gamma-crystallins has been made by computer-graphics model building of several gamma-crystallin sequences based on the atomic co-ordinates of the X-ray determined structure of calf gamma-II crystallin. The complete family of rat gamma-crystallins is compared together with the orthologous protein, gamma 1-2 crystallin, from rat, human and calf lens, and the orthologous protein, gamma 2-1 crystallin, from rat and human lens. In human gamma-crystallins, a major structural difference, the replacement of an arginine by a cysteine, occurs in one of the four-fold repeated folded hairpins, which may affect stability. Sequence variations involving buried residues were observed, leading to small differences in core packing of the different sequences which may be related to their regional location in the lens. Model-building studies also indicate that the surfaces of the different gamma-crystallins vary in number of exposed hydrophobic residues and ion pairs. These differences would affect protein-water interactions and therefore contribute to refractive index. A major variable region of the gamma-crystallin structures involves polar residues surrounding the inter-domain contact and the length of the polypeptide connecting the two domains. An attempt is made to correlate bovine gamma-crystallins which are known to be responsible for cold cataract with the corresponding sequences from rat lens.

Amino Acid Sequence↗
PubMedDate not supplied

Effect of structural variations in cholesteryl-conjugated oligonucleotides on inhibitory activity toward HIV-1.

A number of oligonucleotide analogues containing internucleoside phosphorothioate linkages and a covalently attached cholesteryl residue was synthesized and tested for activity against HIV-1 in cultures of Molt3 cells. Structural features important for high antiviral activity are the presence of a cholesteryl moiety, a run of terminal phosphorothioate groups, and the presence of nucleoside residues. An increase in length of the tether between cholesteryl and phosphorus from six to 14 atoms has no significant effect on antiviral activity, and up to one-half of the internucleoside links in a cholesteryl-conjugated phosphorothioate oligomer and one-third of the internucleoside links in a nonconjugated phosphorothioate can be replaced with phosphodiester links without much change in antiviral activity. However, replacement of nucleoside units in the oligomers by a simple analogue (-OCH2CH2CH2O-) yields inactive or very weakly active compounds, even in the presence of a cholesteryl group. Dose-response patterns for assays in which cholesteryl-conjugated oligomers are added to test cells either simultaneously or subsequently to viral infection are similar for homooligomer derivatives and for oligomers containing "antisense" sequences, suggesting a similarity in mode of action for the two classes of oligomers in this system.

Antiviral Agents↗
PubMed1992

Nonprostanoid prostacyclin mimetics. 3. Structural variations of the diphenyl heterocycle moiety.

4,5-Diphenyl-2-oxazolenonanoic acid (2) and 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (3) were previously identified as nonprostanoid prostacyclin (PGI2) mimetics that inhibit ADP-induced aggregation of human platelets in vitro. The effects on biological activity of substitution and structural modification of the 4- and 5-phenyl rings of 3 was examined. Potency showed a marked sensitivity to the introduction of substituents to these aromatic rings and only the bis-4-methyl derivative 9j, IC50 = 0.34 microM, demonstrated enhanced potency compared to the parent structure 3, IC50 = 1.2 microM. Substitution at the ortho or meta positions of the phenyl rings, replacement by thiopheneyl or cyclohexyl moieties, or constraining in a planar phenanthrene system resulted in compounds that were less effective inhibitors of ADP-induced platelet aggregation. In contrast, variation of the heterocycle moiety revealed a much less stringent SAR and many 5- and 6-membered heterocycles were found to effectively substitute for the oxazole ring of 2 and 3. The diphenylmethyl moiety functioned as an effective isostere for 4,5-diphenylated heterocycles since 13aad showed similar platelet inhibitory activity to 3. With the exception of the 3,4,5-triphenylpyrazole derivative 13g, compounds presenting the (m-ethylphenoxy)acetic acid side chain discovered with 3 demonstrated enhanced potency compared to the analogously substituted alkanoic acid derivative. The structure-activity findings led to a refinement of a model of the nonprostanoid PGI2 mimetic pharmacophore.

Adenosine Diphosphate↗
PubMed2001

Coordination of Lewis acid to eta(2)-enonepalladium(0) leading to continuous structure variation from eta(2)-olefin type to eta(3)-allyl type.

The reaction of alpha,beta-unsaturated carbonyl compounds, a palladium(0) complex, and Lewis acids led to the formation of a new class of complexes showing a wide variety of structures with eta(2)-type and eta(3)-type coordination of the carbonyl compounds. The reaction of Pd(PhCH=CHCOCH(3))(PPh(3))(2) with BF(3).OEt(2) or B(C(6)F(5))(3) quantitatively gave palladium complexes 1a,b having BX(3)-coordinated eta(2)-enonepalladium structure, as revealed by X-ray structure analysis of the B(C(6)F(5))(3) adduct 1b. On the other hand, the reaction of Pd(PhCH=CHCHO)(PPh(3))(2) with BF(3).OEt(2) or B(C(6)F(5))(3) gave distorted zwitterionic eta(3)-allylpalladium complexes 3a,b, where the Pd-carbonyl carbon distance in 3a (2.413(4) A) is much shorter than that (2.96(1) A) in 1b. The values of the P-P coupling constant and (13)C chemical shift for carbonyl carbon are useful criteria for predicting how the eta(3)-coordination mode contributes to the structure of the enone-palladium-Lewis acid system. Molecular orbital calculations on the series of model complexes suggest that orbital overlap in the highest occupied molecular orbital between the palladium and carbonyl carbon is enlarged by coordination of the Lewis acid to the carbonyl group. Palladium-catalyzed conjugate addition of R-M (R-M = AlMe(3), AlEt(3), ZnEt(2)) and its plausible reaction path are also reported.

Journal Article↗
PubMed2003

Structural variation and inhibitor binding in polypeptide deformylase from four different bacterial species.

Polypeptide deformylase (PDF) catalyzes the deformylation of polypeptide chains in bacteria. It is essential for bacterial cell viability and is a potential antibacterial drug target. Here, we report the crystal structures of polypeptide deformylase from four different species of bacteria: Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Escherichia coli. Comparison of these four structures reveals significant overall differences between the two Gram-negative species (E. coli and H. influenzae) and the two Gram-positive species (S. pneumoniae and S. aureus). Despite these differences and low overall sequence identity, the S1' pocket of PDF is well conserved among the four enzymes studied. We also describe the binding of nonpeptidic inhibitor molecules SB-485345, SB-543668, and SB-505684 to both S. pneumoniae and E. coli PDF. Comparison of these structures shows similar binding interactions with both Gram-negative and Gram-positive species. Understanding the similarities and subtle differences in active site structure between species will help to design broad-spectrum polypeptide deformylase inhibitor molecules.

Amidohydrolases↗
PubMed1985

A theoretical study of the effect of structural variations on the biochemical reactivity of yeast tRNAPhe and yeast tRNAAsp.

The ASIF index which combines both steric and electronic factors is applied to the comparative study of the reactivity of yeast tRNAAsp and yeast tRNAPhe using the coordinates deduced from their crystal structures. The results compared with the known experimental reactivities in solution are somewhat less perfect for tRNAAsp than for tRNAPhe. The reasons for this situation are probably related to the differences existing between the structures of tRNAAsp in the crystal and in solution.

Alkylation↗
PubMed1993

Structural variation in the O-specific polysaccharides of Klebsiella pneumoniae serotype O1 and O8 lipopolysaccharide: evidence for clonal diversity in rfb genes.

The O-polysaccharide fraction of the lipopolysaccharide from Klebsiella pneumoniae serotype O8 was found to comprise two galactose-containing homopolymers. Structural analysis, using chemical and high-field nuclear magnetic resonance (NMR) techniques, established that the K. pneumoniae O8 polysaccharides are composed of the linear, disaccharide repeating units [formula: see text] K. pneumoniae O8 mutant RFK-1 was isolated by resistance to phage KO1-2; strain RFK-1 expressed only D-galactan I-OAc. The 1H- and 13C-NMR resonances from this O-polysaccharide indicate that all of the O-acetyl groups within the K. pneumoniae O8 polysaccharide are carried on D-galactan I and O-acetylation occurs only on the beta-D-galactofuranose residues; 60% of the available beta-D-galactofuranose residues are non-acetylated. The O-acetylation of the remaining residues is equally distributed between the O-2 and O-6 positions. The carbohydrate backbone structures in the O8 polysaccharide are identical to D-galactan I and II expressed by K. pneumoniae O1, accounting for the antigenic cross-reaction between strains belonging to serotypes O1 and O8. However, the O1 polysaccharides are not acetylated and the O-acetyl groups present in the K. pneumoniae serotype O8 polysaccharides provide a structural basis for their recognition as distinct serotypes. The rfb (O-polysaccharide biosynthesis) gene cluster of K. pneumoniae serotype O1 determines the synthesis of D-galactan I. rfbKpO1-specific gene probes were used to examine conservation in the rfb gene clusters of other K. pneumoniae serotypes which produce D-galactan I. Six O1 strains were examined and all showed hybridization with rfbKpO1 probes under conditions of high stringency. Three serotype O2 strains produce D-galactan I and these strains also contained DNA sequences recognized by rfbKpO1 probes under high stringency. The physical maps of these homologous rfb chromosomal regions showed some polymorphism. Surprisingly, the rfbKpO8 region from K. pneumoniae serotype O8 was only recognized by rfbKpO1 probes under low-stringency hybridization conditions, providing evidence for two substantially different clonal groups of rfb genes from K. pneumoniae strains with structurally related O-antigens.

Acetylation↗
PubMed1989

Phenotypic effects of apolipoprotein structural variation on lipid profiles. I. APO H and quantitative lipid measures in the healthy women study.

Apolipoprotein H (APO H), also known as beta 2-glycoprotein I, has been identified as a protein component of the major lipoprotein density fractions in human plasma. Recently, genetically determined structural polymorphism in white and black populations has been documented for this apolipoprotein. There are three common alleles in whites and blacks and a fourth allele found mainly in blacks. Family data confirm the autosomal codominant pattern of inheritance for the APO H structural gene. Little is known about the function of APO H, but it has demonstrated both lipid and platelet involvement. In this study we investigate the effect of APO H phenotypes on quantitative lipid measures in a group of 443 white women being followed through menopause for changes in cardiovascular risk. At baseline all women were premenopausal. None of the APO H phenotypes showed a statistically significant effect on lipid measures in this population.

Adult↗
PubMed1999

Structure and structural variations of the Escherichia coli 30 S ribosomal subunit as revealed by three-dimensional cryo-electron microscopy.

A three-dimensional reconstruction of the 30 S subunit of the Escherichia coli ribosome was obtained at 23 A resolution. Because of the improved resolution, many more structural details are seen as compared to those obtained in earlier studies. Thus, the new structure is more suitable for comparison with the 30 S subunit part of the 70 S ribosome, whose structure is already known at a better resolution. In addition, we observe relative and, to some extent, independent movements of three main structural domains of the 30 S subunit, namely head, platform and the main body, which lead to partial blurring of the reconstructed volume. An attempt to subdivide the data set into conformationally defined subsets reveals the existence of conformers in which these domains have different orientations with respect to one another. This result suggests the existence of dynamic properties of the 30 S subunit that might be required for facilitating its interactions with mRNA, tRNA and other ligands during protein biosynthesis.

Bacterial Proteins↗