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PubMed1984

DNA structural variations produced by actinomycin and distamycin as revealed by DNAase I footprinting.

The technique of DNAase I footprinting has been used to investigate preferred binding sites for actinomycin D and distamycin on a 160-base-pair DNA fragment from E. coli containing the tyr T promoter sequence. Only sites containing the dinucleotide step GpC are protected by binding of actinomycin, and all such sites are protected. Distamycin recognizes four major regions rich in A + T residues. Both antibiotics induce enhanced rates of cleavage at certain regions flanking their binding sites. These effects are not restricted to any particular base sequence since they are produced in runs of A and T by actinomycin and in GC-rich sequences by distamycin. The observed increases in susceptibility to nuclease attack are attributed to DNA structural variations induced in the vicinity of the ligand binding site, most probably involving changes in the width of the helical minor groove.

Base Sequence↗
PubMed2004

Improvement of comparative model accuracy by free-energy optimization along principal components of natural structural variation.

Accurate high-resolution refinement of protein structure models is a formidable challenge because of the delicate balance of forces in the native state, the difficulty in sampling the very large number of alternative tightly packed conformations, and the inaccuracies in current force fields. Indeed, energy-based refinement of comparative models generally leads to degradation rather than improvement in model quality, and, hence, most current comparative modeling procedures omit physically based refinement. However, despite their inaccuracies, current force fields do contain information that is orthogonal to the evolutionary information on which comparative models are based, and, hence, refinement might be able to improve comparative models if the space that is sampled is restricted sufficiently so that false attractors are avoided. Here, we use the principal components of the variation of backbone structures within a homologous family to define a small number of evolutionarily favored sampling directions and show that model quality can be improved by energy-based optimization along these directions.

Models, Molecular↗
PubMed2003

Colony-structure variation and interspecific competitive ability in the invasive Argentine ant.

The success of some invasive species may depend on phenotypic changes that occur following introduction. In Argentine ants (Linepithema humile) introduced populations typically lack intraspecific aggression, but native populations display such behavior commonly. We employ three approaches to examine how this behavioral shift might influence interspecific competitive ability. In a laboratory experiment, we reared colonies of Forelius mccooki with pairs of Argentine ant colonies that either did or did not exhibit intraspecific aggression. F. mccooki reared with intraspecifically non-aggressive pairs of Argentine ants produced fewer eggs, foraged less actively, and supported fewer living workers than those reared with intraspecifically aggressive pairs. At natural contact zones between competing colonies of L. humile and F. mccooki, the introduction of experimental Argentine ant colonies that fought with conspecific field colonies caused L. humile to abandon baits in the presence of F. mccooki, whereas the introduction of colonies that did not fight with field colonies of Argentine ants resulted in L. humile retaining possession of baits. Additional evidence for the potential importance of colony- structure variation comes from the Argentine ant's native range. At a site along the Rio de la Plata in Argentina, we found an inverse relationship between ant richness and density of L. humile (apparently a function of local differences in colony structure) in two different years of sampling.

Aggression↗
PubMed1988

The central projections of the stretch receptor neurons of crayfish: structure, variation, and postembryonic growth.

Each stretch receptor neuron (SR) of the crayfish abdomen projects from its peripherally located soma an axon that enters the CNS through the second nerve (N2) of its segmental ganglion. Co2+ backfills of N2 revealed that this axon bifurcates, sending one branch to the brain and the other to the terminal abdominal ganglion. Each axon makes many short lateral branches as it traverses each of the other segmental ganglia, and has 2 major arborizations--one in the tritocerebrum of the brain and the other in the terminal abdominal ganglion, G6. These projections to G6 are described in detail. Individual SR axons from different segments were impaled in G6 with a Lucifer yellow-filled microelectrode, identified physiologically, and then filled to discover their structures. In a sample of more than 50 SR neurons, no systematic structural differences between the projections of phasic SR neurons and tonic SR neurons were observed. Three kinds of structural variability occurred in these projections to G6: unusual primary axon shape, long primary axon, and large terminal varicosities. Comparisons of SR neurons that originated in different segments revealed a segmental gradient in the probability of each structural variant. SR neurons from more anterior segments were more likely to show these structural variations. Comparisons of these variations in crayfish of different sizes showed that unusual primary axon shape and long primary axons were more probable in large crayfish than in small ones. Therefore, these variations are probably the products of postembryonic growth of the nervous system.

Animals↗
PubMed2005

Evolutionary plasticity of protein families: coupling between sequence and structure variation.

In this work we examine how protein structural changes are coupled with sequence variation in the course of evolution of a family of homologs. The sequence-structure correlation analysis performed on 81 homologous protein families shows that the majority of them exhibit statistically significant linear correlation between the measures of sequence and structural similarity. We observed, however, that there are cases where structural variability cannot be mainly explained by sequence variation, such as protein families with a number of disulfide bonds. To understand whether structures from different families and/or folds evolve in the same manner, we compared the degrees of structural change per unit of sequence change ("the evolutionary plasticity of structure") between those families with a significant linear correlation. Using rigorous statistical procedures we find that, with a few exceptions, evolutionary plasticity does not show a statistically significant difference between protein families. Similar sequence-structure analysis performed for protein loop regions shows that evolutionary plasticity of loop regions is greater than for the protein core.

Amino Acids↗
PubMed2002

Influence of structural variations in peptidomimetic 4-amidinophenylalanine-derived thrombin inhibitors on plasma clearance and biliary excretion in rats.

PURPOSE: Systemic and hepato-biliary clearance of peptidomimetic thrombin inhibitors of the 4-amidinophenylalanine amide-type, derived from NAPAP (Nalpha-[2-naphthylsulfonyl-glycyl]-4-amidinophenylalanine-piperidide) by substituting Gly in P2 for natural and unnatural amino acids or by varying the C- and N-terminal moieties. resp., were investigated. METHODS: Concentrations of the compounds administered as intravenous bolus injection at a dose of 1 mg/kg to bile duct-cannulated rats were determined in plasma and bile samples collected over 4 hours using reversed-phase HPLC. RESULTS: NAPAP and the derivatives with additional charged groups are comparatively hydrophilic compounds. For NAPAP and most of the derivatives the biliary clearance accounted for a high percentage of the rapid systemic plasma clearance. Derivatives 2a-c with a second basic group in P2 position showed lower systemic and biliary clearance compared to NAPAP, whereas their cumulative biliary excretion after a period of 120 min was less affected. Bis-benzamidine derivatives 4a and 5 with the second amidino group in the N-terminal moiety had the lowest biliary clearance. Additional carboxylic groups reduced the systemic and biliary clearance only as free amidinophenylalanine carboxyl in 3a and 5. No influence compared to NAPAP was observed for 2d with a free carboxyl group in P2 position. CONCLUSIONS: The weak correlation of the log P values of the compounds with the clearance parameters indicates the influence of structural variations, especially of charged groups, in this series of compounds rather than overall lipophilicity on hepato-biliary elimination mediated by hepatocellular transporters.

Animals↗
PubMed2006

Structural variation of the human genome.

There is growing appreciation that the human genome contains significant numbers of structural rearrangements, such as insertions, deletions, inversions, and large tandem repeats. Recent studies have defined approximately 5% of the human genome as structurally variant in the normal population, involving more than 800 independent genes. We present a detailed review of the various structural rearrangements identified to date in humans, with particular reference to their influence on human phenotypic variation. Our current knowledge of the extent of human structural variation shows that the human genome is a highly dynamic structure that shows significant large-scale variation from the currently published genome reference sequence.

Genetic Variation↗
PubMed1987

Evidence for diverse structural variations of the forms of human FSH within and between pituitaries.

The biological activity of FSH in vitro (B-vitro) was compared with its radioimmunological (RIA) activity in 38 pituitary extracts from men and women. The B-vitro method was based upon the estimation of oestradiol produced by cultured Sertoli cells from 10-day-old rats. The mean B-vitro/RIA ratios for FSH of men and young and elderly women were almost identical. The mean values of median charge of the forms of FSH differed significantly between the three groups of human adults. The B-vitro/RIA ratio of different forms of FSH, separated by electrophoresis of 14 individual pituitary extracts, was higher for less negatively charged than for more negatively charged forms. Some forms of FSH with the same charge and separated from different pituitary extracts, e.g. from a young and an elderly woman, had significantly different B-vitro/RIA ratios. This ratio, thus, was not related to the charge per se of the hormone. However, the relation between the B-vitro/RIA ratio and the charge of FSH was similar for individual pituitary extracts when charge was expressed in relation to median charge. The results suggest that different molecular structural variations of FSH are involved in the polymorphisms observed within and between individual pituitaries. In human adults, the variation of FSH between the pituitaries mainly affects the metabolic clearance rate (MCR) of the hormone, whereas the variation within the individual pituitary affects both the MCR of the hormone and its biological effect at the target cell.

Adolescent↗
PubMed2005

Contribution of regulatory and structural variations in APOE to predicting dyslipidemia.

The objective of this study was to evaluate 1) whether non single nucleotide polymorphisms-coding (non-cSNP) in the apolipoprotein E gene (APOE) identified by resequencing studies contribute to statistically explaining dyslipidemia if variations in the two cSNPs in exon 4 that define the 2, 3, and 4 alleles are ignored, and 2) whether the contribution of these additional SNPs persists when variations in the cSNPs are considered. We used an ecological, multiple-population, data-mining strategy to identify single-SNP and two-SNP genotypes that distinguish between high and low levels of plasma lipids in three training samples, European-Americans from Rochester, MN, African-Americans from Jackson, MS, and Europeans from North Karelia, Finland. We found that a pair of SNPs located in the 5' region define genotypes A560T832/A560T832, A560T832/A560G832, and A560T832/T560T832, which distinguish between high and low levels of HDL-cholesterol (HDL-C), triglycerides (TG), and/or total cholesterol (T-C). The A560T832/- genotypes predicted high TG and high T-C in both genders in a large independent test sample from Copenhagen, Denmark. Prediction of high T-C in the Danish females was dependent on genotypes defined by the cSNPs. Our study suggests that both regulatory and structural variations should be considered when evaluating the utility of APOE for predicting dyslipidemia in the population at large.

Black or African American↗
PubMed1999

The pH-dependent structural variation of complementarity-determining region H3 in the crystal structures of the Fv fragment from an anti-dansyl monoclonal antibody.

The Fv fragment from an anti-dansyl antibody was optimally crystallized into two crystal forms having slightly different lattice dimensions at pH 5.25 and 6.75. The two crystal structures were determined and refined at high resolution at 112 K (at 1.45 A for the crystal at pH 5.25 and at 1.55 A for that at pH 6.75). In the two crystal structures, marked differences were identified in the first half of CDRH3 s having an amino acid sequence of Ile95H-Tyr96H-Tyr97H-His98H-Tyr99H-Pro1 00H-Trp100aH-Phe100bH-Ala101H- Tyr102H. NMR pH titration experiments revealed the p Kavalues of four histidine residues (His27dL, His93L, His55H and His98H) exposed to solvent. Only His98H (p Ka=6.3) completely changed its protonation state between the two crystallization conditions. In addition, the environmental structures including hydration water molecules around the four histidine residues were carefully compared. While the hydration structures around His27dL, His93L and His55H were almost invariant between the two crystal structures, those around His98Hs showed great difference in spite of the small conformational difference of His98H between the two crystal structures. These spectroscopic and crystallographic findings suggested that the change in the protonation state in His98H was responsible for the structural differences between pH 5.25 and 6.75. In addition, the most plausible binding site of the dansyl group was mapped into the present structural models with our previous NMR experimental results. The complementarity-determining regions H1, H3 and the N-terminal region in the VH domain formed the site. The side-chain of Tyr96H occupied the site and interacted with Phe27H of H1, giving a clue for the binding mode of the dansyl group in the site.

Antibodies, Monoclonal↗
PubMed1988

Genetic studies of low abundance human plasma proteins. VIII. Inherited structural variation in antithrombin III.

Genetically determined structural polymorphism of antithrombin III has been observed using ultra narrow pH polyacrylamide isoelectric focusing gels, followed by immunoblotting. The products of three alleles at the antithrombin III structural locus have been detected in normal U.S. white and black blood donors. The frequencies of the three alleles, AT III* 1, AT III* 2 and AT III* 3, respectively, are: 0.878, 0.103, 0.019 in whites and 0.916, 0.068, 0.016 in blacks. Family data from a large number of families establish an autosomal codominant pattern of inheritance of the three alleles.

Alleles↗
PubMed2002

Normal structure, variations, and anomalies of the pancreaticobiliary ducts of Koreans: a nationwide cooperative prospective study.

BACKGROUND: This study evaluated the normal pancreaticobiliary ducts of Koreans and assessed the frequency and pattern of variations and anomalies of these structures. METHODS: A prospective, nationwide multicenter study was performed in which 10 university hospitals in Korea participated from March 1997 to June 1999. A total 10,243 patients undergoing ERCP were enrolled. RESULTS: The mean (SD) maximal and midportion diameters in millimeters of the common hepatic duct were, respectively, 6.1 (1.8) and 5.3 (1.6). The mean maximal and midportion diameters (mm) of the common bile duct were, respectively, 6.4 (1.8) and 5.5 (1.7). The mean maximal and midportion diameters (mm) of the main pancreatic duct in the head, body and tail were, respectively, 3.2 (1.1), 2.7 (1.0), and 2.5 (2.3); and, respectively, 2.2 (0.9), 1.6 (0.7) and 1.4 (0.6). Pancreaticobiliary duct diameters for patients above the age of 40 were greater than those of patients less than 40 years of age (p < 0.05). The frequency of choledochal cyst and anomalous union of the pancreaticobiliary ducts were, respectively, 0.32% and 4.1%. Pancreas divisum and annular pancreas were found, respectively, in 0.49% and 0.05%. CONCLUSIONS: A knowledge of normal pancreaticobiliary ductal structures as well as the frequency and pattern of variations including anomalies is essential for the diagnosis and treatment of pancreaticobiliary disorders.

Adolescent↗
PubMed1991

Structural variation and (+)-amphetamine-like discriminative stimulus properties.

Rats were trained to discriminate (+)-amphetamine sulfate (5.43 mumol/kg, 1 mg/kg) from saline in a food-reinforced, two-lever drug discrimination paradigm. Side chain variations of the amphetamine molecular structure were analyzed for their effects on the discriminative stimulus properties of this prototype central nervous system stimulant. Partial generalization was observed for the alpha-ethyl homologue of (+)-amphetamine, (+)-AEPEA, and for 2-aminoindan (AI), while 5,6-methylenedioxy-2-aminoindan (MDAI) elicited only saline-appropriate responding. By contrast, 2-amino-1,2-dihydronaphthalene (ADN) and 2-aminotetralin (AT) completely substituted for (+)-amphetamine. Relative to the training drug, ADN was 1/4 as potent and AT was 1/8 as potent. The S-(-)-isomer of ADN was found to be responsible for the (+)-amphetamine-like discriminative properties of the racemate. The results suggest that constraining or extending the alpha-alkyl substituent of (+)-amphetamine has a deleterious effect on the ability of the resulting analogue to adopt the active conformation of (+)-amphetamine, thereby diminishing its characteristic discriminative stimulus properties.

Animals↗
PubMed2000

Structural variations of the VWA locus in humans and comparison with non-human primates.

The HUMVWA locus was examined in 160 samples from the Japanese population. A total of 142 fragments were sequenced, and the counterpart sequences were also determined in non-human primates. In humans, 10 different alleles were found; they could be grouped into seven allelic classes based on the total number of repeats. No variation was observed in the alleles 17, 18 and 19, which showed consensus sequence structures and in the allele 14, which showed a different structure. New variation was found in alleles 15, 16, and 20, which had differences occurred in a basic (TCTA)(TCTG)(n) repeat in the 5' side. The counterpart fragments were successfully amplified in three species (chimpanzees, gorilla, and orangutan) out of four kinds of anthropoids, three species (rhesus macaques, Japanese macaques, and green monkey) out of four kinds of old world monkeys, but not in one species of either new world monkey or prosimian. The sizes of the fragments distributed from 92 to 180 bp in non-human primates and showed allelic size differences in four species. The sequence of the 5' flanking region followed by primer sequences in humans and anthropoids, which consisted of 19 bp, was identical in all, but differed from that in old world monkeys. The basic repeat motifs of humans and anthropoids consisted of TCTA, TCTG, and TCCA but that of old world monkeys consisted of TCTG, TCCG and TCCA The structures of humans and anthropoids were essentially similar, but with characteristic difference in each species. Differences in the allelic structures of old world monkeys were complex. Seven different alleles were observed in two rhesus and two Japanese macaques and one type of allele was observed in two green monkeys. Duplication of more than two repeat units of 4 bp was found in an allele of an old world monkey. These data illuminate interesting features of mutational changes in STRs during the long generations and also some insight into evolutional aspects of primates.

Animals↗
PubMed1999

High resolution solution structure of apo calcyclin and structural variations in the S100 family of calcium-binding proteins.

The three-dimensional solution structure of apo rabbit lung calcyclin has been refined to high resolution through the use of heteronuclear NMR spectroscopy and 13C, 15N-enriched protein. Upon completing the assignment of virtually all of the 15N, 13C and 1H NMR resonances, the solution structure was determined from a combination of 2814 NOE-derived distance constraints, and 272 torsion angle constraints derived from scalar couplings. A large number of critical inter-subunit NOEs (386) were identified from 13C-select, 13C-filtered NOESY experiments, providing a highly accurate dimer interface. The combination of distance geometry and restrained molecular dynamics calculations yielded structures with excellent agreement with the experimental data and high precision (rmsd from the mean for the backbone atoms in the eight helices: 0.33 A). Calcyclin exhibits a symmetric dimeric fold of two identical 90 amino acid subunits, characteristic of the S100 subfamily of EF-hand Ca(2+)-binding proteins. The structure reveals a readily identified pair of putative sites for binding of Zn2+. In order to accurately determine the structural features that differentiate the various S100 proteins, distance difference matrices and contact maps were calculated for the NMR structural ensembles of apo calcyclin and rat and bovine S100B. These data show that the most significant variations among the structures are in the positioning of helix III and in loops, the regions with least sequence similarity. Inter-helical angles and distance differences for the proteins show that the positioning of helix III of calcyclin is most similar to that of bovine S100B, but that the helix interfaces are more closely packed in calcyclin than in either S100B structure. Surprisingly large differences were found in the positioning of helix III in the two S100B structures, despite there being only four non-identical residues, suggesting that one or both of the S100B structures requires further refinement.

Animals↗