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At least 1,153 records · Page 64Linked to original sources

PubMed2003

Recognition of DNA interstrand cross-link of antitumor cisplatin by HMGB1 protein.

Several proteins that specifically bind to DNA modified by cisplatin, including those containing HMG-domains, mediate antitumor activity of this drug. Oligodeoxyribonucleotide duplexes containing a single, site-specific interstrand cross-link of cisplatin were probed for recognition by the rat chromosomal protein HMGB1 and its domains A and B using the electrophoretic mobility-shift assay. It has been found that the full-length HMGB1 protein and its domain B to which the lysine-rich region (seven amino acid residues) of the A/B linker is attached at the N-terminus (the domain HMGB1b7) specifically recognize DNA interstrand cross-linked by cisplatin. The affinity of these proteins to the interstrand cross-link of cisplatin is not very different from that to the major 1,2-GG intrastrand cross-link of this drug. In contrast, no recognition of the interstrand cross-link by the domain B lacking this region or by the domain A with or without this lysine-rich region attached to its C-terminus is noticed under conditions when these proteins readily bind to 1,2-GG intrastrand adduct. A structural model for the complex formed between the interstrand cross-linked DNA and the domain HMGB1b7 was constructed and refined using molecular mechanics and molecular dynamics techniques. The calculated accessible areas around the deoxyribose protons correlate well with the experimental hydroxyl radical footprint. The model suggests that the only major adaptation necessary for obtaining excellent surface complementarity is extra DNA unwinding (approximately 40 degrees ) at the site of the cross-link. The model structure is consistent with the hypothesis that the enhancement of binding affinity afforded by the basic lysine-rich A/B linker is a consequence of its tight binding to the sugar-phosphate backbone of both DNA strands.

Amino Acid Motifs↗

PubMed2004

The potentials of conditional optimization in phasing and model building of protein crystal structures.

Model building is a pivotal step in protein-structure determination, because with an atomic model available the vast amount of geometrical prior knowledge may be applied to the structure-determination process. Here, conditional optimization, a method that does not require interpretation of the electron-density map, is described. Instead, this method refines loose atoms for which all chemical interpretations are considered simultaneously using an N-particle formalism. This method bears the potential of introducing the geometrical data much earlier in the structure-determination process, i.e. well before an interpretable electron-density map has been obtained. Here, results from two tests are presented: automated model building of three proteins with diffraction data extending to 2.4-3.0 A resolution and ab initio phasing of a small four-helical bundle with diffraction data to 2.0 A resolution. Models built automatically by the widely used programs ARP/wARP and RESOLVE and those from conditional optimization per se, without discrete modelling steps, had comparable phase quality and completeness, except in loop regions, which are poorly modelled by the current force field in conditional optimization. Optimization of multiple random starting models by conditional optimization yielded models revealing the four helices of the four-helical bundle.

Bacterial Outer Membrane Proteins↗

PubMed1997

Lead discovery of inhibitors of the dihydrofolate reductase domain of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase.

A three-dimensional structure model of the dihydrofolate reductase (DHFR) domain of the bifunctional DHFR-thymidylate synthase of Plasmodium falciparum was used as a basis for computational screening of commercially available compounds for candidate inhibitors. Compounds which can stably dock to the model with strong ionic hydrogen bonds via protonation by an aspartic acid residue at the bottom of the active site were identified through docking simulation. Among compounds thus identified, 21 were assayed for inhibitory activity towards the recombinant DHFR domain. Two compounds, 2-amino-1,4-dihydro-4,4,7,8-tetramethyl-s-triazino(1,2-a)benzimida zole and Trp-P-2, inhibited the recombinant P. falciparum DHFR domain with Ki values of 0.54 and 8.7 microM, respectively. Kinetic analysis showed that these compounds competitively inhibited the enzyme with respect to the substrate dihydrofolate. These findings support the validity of both the modeled structure and the docking results. Furthermore, these compounds serve as leads for developing new DHFR inhibitors, since their skeletal structures are different from any of known DHFR inhibitors. This paper also reveals a new biological activity of Trp-P-2, a potent mutagen.

Animals↗

PubMed2003

Improved catalytic efficiency and active site modification of 1,4-beta-D-glucan glucohydrolase A from Thermotoga neapolitana by directed evolution.

Thermotoga neapolitana 1,4-beta-d-glucan glucohydrolase A preferentially hydrolyzes cello-oligomers, such as cellotetraose, releasing single glucose moieties from the reducing end of the cello-oligosaccharide chain. Using directed evolution techniques of error-prone PCR and mutant library screening, a variant glucan glucohydrolase has been isolated that hydrolyzes the disaccharide, cellobiose, at a 31% greater rate than its wild type (WT) predecessor. The mutant library, expressed in Escherichia coli, was screened at 85 degrees C for increased hydrolysis of cellobiose, a native substrate rather than a chromogenic analog, using a continuous, thermostable coupled enzyme assay. The V(max) for the mutant was 108 +/- 3 units mg(-1), whereas that of the WT was 75 +/- 2 units mg(-1). The K(m) for both proteins was nearly the same. The k(cat) for the new enzyme increased by 31% and its catalytic efficiency (k(cat)/K(m)) for cellobiose also rose by 31% as compared with the parent. The nucleotide sequence of two positive clones and two null clones identified 11 single base shifts. The nucleotide transition in the most active clone caused an isoleucine to threonine amino acid substitution at position 170. Structural models for I170T and WT proteins were derived by sequence homology with Protein Data Bank code 1BGA from Paenibacillus polymyxa. Analysis of the WT and I170T model structures indicated that the substitution in the mutant enzyme repositioned the conserved catalytic residue Asn-163 and reconfigured entry to the active site.

Amino Acid Sequence↗

PubMed1999

Conserved features of Y RNAs revealed by automated phylogenetic secondary structure analysis.

Y RNAs are small 'cytoplasmic' RNAs which are components of the Ro ribonucleoprotein (RNP) complex. The core of this complex, which is found in the cell nuclei of higher eukaryotes as well as the cytoplasm, is composed of a complex between the 60 kDa Ro protein and Y RNAs. Human cells contain four distinct Y RNAs (Y1, Y3, Y4 and Y5), while other eukaryotes contain a variable number of Y RNA homologues. When detected in a particular species, the Ro RNP has been present in every cell type within that particular organism. This characteristic, along with its high conservation among vertebrates, suggests an important function for Ro RNP in cellular metabolism; however, this function has not yet been definitively elucidated. In order to identify conserved features of Y RNA sequences and structures which may be directly involved in Ro RNP function, a phylogenetic comparative analysis of Y RNAs has been performed. Sequences of Y RNA homologues from five vertebrate species have been obtained and, together with previously published Y RNA sequences, used to predict Y RNA secondary structures. A novel RNA secondary structure comparison algorithm, the suboptimal RNA analysis program, has been developed and used in conjunction with available algorithms to find phylogenetically conserved secondary structure models for YI, Y3 and Y4 RNAs. Short, conserved sequences within the Y RNAs have been identified and are invariant among vertebrates, consistent with a direct role for Y RNAs in Ro function. A subset of these are located wholly or partially in looped regions in the Y3 and Y4 RNA predicted model structures, in accord with the possibility that these Y RNAs base pair with other cellular nucleic acids or are sites of interaction between the Ro RNP and other macromolecules.

Animals↗

PubMed1993

Mechanism of phosphate adsorption to a three-dimensional structure of boehmite in the presence of bovine serum albumin.

A new microcrystalline boehmite (tentatively named PT-A) was synthesized as an efficient phosphate adsorbent to replace aluminum hydroxide gel. The characteristic structure of PT-A was examined by nitrogen adsorption/desorption, X-ray diffraction, deviation microscopy, and scanning electron microscopy to establish a pore structural model of PT-A. With this model structure, the details of the mechanism of interaction between PT-A and phosphate in the presence of bovine serum albumin (BSA) are discussed. PT-A is a spherical particle with a diameter of approximately 100 microns and a porous surface structure, and its inside is packed with boehmite microcrystals (crystallite size, 2 nm). PT-A has three types of pores in its structure: a micropore with a narrow size-distribution, a mesopore with a broad size-distribution, and a macropore (radii of pores are 0.7, 1-20, and approximately 300 nm, respectively). When phosphate was incubated with PT-A in human gastric and intestinal juices or in an aqueous solution containing BSA, the amounts of phosphate adsorbed by PT-A were not affected by the presence of proteins. The nitrogen adsorption/desorption isotherms and energy dispersive X-ray analyses demonstrated that phosphate could diffuse to the smaller tunnels freely even if the external surface of PT-A was covered with BSA. It was also demonstrated that the main site of adsorption for phosphate was in micropores of PT-A, whereas BSA was adsorbed only to the external surface and none entered inside smaller tunnels consisting of micro- and mesopores.

Adsorption↗

PubMed1987

The consistency of peer and parent influences on tobacco, alcohol, and marijuana use among young adolescents.

The purpose of this study was to determine the degree to which the use of tobacco, alcohol, and marijuana by young adolescents can be described using a common theoretical model. Structural models were created in which psychosocial variables hierarchically predicted the use of each substance. The fit of a model in which paths from predictor variables were constrained to be equal was not inferior in any meaningful way to that of a model in which all path coefficients were freely estimated, thus suggesting that use of tobacco, alcohol, and marijuana by young adolescents may be considered to be a unitary phenomenon. A simplified model, in which these substances were combined into a single latent variable, showed a good fit. The results of these analyses suggest that it may be beneficial to consider adolescent substance use to be a unitary phenomenon.

Adolescent↗

PubMed1990

Structural analysis of the 5' domain of the HeLa 18S ribosomal RNA by chemical and enzymatic probing.

The secondary structure of HeLa 18S rRNA was investigated by a combination of chemical and enzymatic probing techniques. Using four chemical reagents (DMS*, kethoxal, DEPC and CMCT) which react specifically with unpaired bases and two nucleases (RNase T1 and cobra venom nuclease) which cleave the ribopolynucleotides at unpaired guanines and helical segments, we have analyzed the secondary structure of the 5' domain of 18S rRNA isolated from HeLa 40S ribosomal subunits. The sites at which chemical modifications and nuclease cleavages occurred were identified by primer extension using synthetic deoxyoligonucleotides and reverse transcriptase. These studies led to the deduction of an intra-RNA pairing pattern from the available secondary structure models based on comparative sequence analysis. Apart from the general canonical pairing we have identified noncanonical U-U, G-A, A-G, A-C, C-A and G-G pairing in HeLa 18S rRNA. The differential reactivity of bases to chemical reagents has enabled us to predict the possible configuration of these bases in some of the noncanonical pairing. The absence of chemical reactivities and cobra venom nuclease sensitivity in the terminal loops of helices 6 and 12 indicate a tertiary interaction unique to HeLa 18S rRNA. We have confirmed the existence of the complex tertiary folding recently proposed (Gutell and Woese 1990 Proc. Natl. Acad. Sci. 87, 663-667) for the universally conserved helix 19 in HeLa 18S rRNA. The complementarity of chemical modifications and enzymatic cleavages provided experimental evidence for the proposal of a model structure for the 655 nucleotides of the 5' domain of HeLa 18S rRNA.

Base Sequence↗

PubMed1999

Experimental and theoretical characterization of structure in thin disordered films.

The electron microscope provides an ideal environment for the structural analysis of small volumes of amorphous and polycrystalline materials by enabling the collection of scattering information as a function of energy loss and momentum transfer. The scattered intensity at zero energy loss can be readily processed to a reduced density function, providing information on nearest-neighbour distances and bond angles. A method for collecting and processing the scattered intensity, which allows for the collection of an energy-loss spectrum for a range of momentum transfers, is discussed. A detailed structural determination from a reduced density function alone is difficult and it is shown that a more detailed structural model can be obtained by combining the experimental reduced density function with model structures obtained from molecular dynamics based on first-principles quantum mechanics. This method is applied to tetrahedral amorphous carbon, as an example of a monatomic network, and to aluminium nitride, as a prototype for a binary amorphous alloy.

Journal Article↗

PubMed2004

Characterization of glycerol trinitrate reductase (NerA) and the catalytic role of active-site residues.

Glycerol trinitrate reductase (NerA) from Agrobacterium radiobacter, a member of the old yellow enzyme (OYE) family of oxidoreductases, was expressed in and purified from Escherichia coli. Denaturation of pure enzyme liberated flavin mononucleotide (FMN), and spectra of NerA during reduction and reoxidation confirmed its catalytic involvement. Binding of FMN to apoenzyme to form the holoenzyme occurred with a dissociation constant of ca. 10(-7) M and with restoration of activity. The NerA-dependent reduction of glycerol trinitrate (GTN; nitroglycerin) by NADH followed ping-pong kinetics. A structural model of NerA based on the known coordinates of OYE showed that His-178, Asn-181, and Tyr-183 were close to FMN in the active site. The NerA mutation H178A produced mutant protein with bound FMN but no activity toward GTN. The N181A mutation produced protein that did not bind FMN and was isolated in partly degraded form. The mutation Y183F produced active protein with the same k(cat) as that of wild-type enzyme but with altered K(m) values for GTN and NADH, indicating a role for this residue in substrate binding. Correlation of the ratio of K(m)(GTN) to K(m)(NAD(P)H), with sequence differences for NerA and several other members of the OYE family of oxidoreductases that reduce GTN, indicated that Asn-181 and a second Asn-238 that lies close to Tyr-183 in the NerA model structure may influence substrate specificity.

Binding Sites↗

PubMed1989

Learning arm kinematics and dynamics.

In this review I have discussed how the form of representation used in internal models of the motor apparatus affects how and what a system can learn. Tabular models and structured models have benefits and drawbacks. Structured models incorporate knowledge of the structure of the controlled motor apparatus. If that knowledge is correct, or close to the actual system structure, the structured models will support global generalization and rapid, efficient learning. Tabular models can play an important role in learning to control systems when either the system structure is not known or only known approximately. Tabular models are general and flexible. Techniques for combining these different representations to attain the benefits of both are currently under investigation. In the control of multijoint systems such as the human arm, internal models of the motor apparatus are necessary to interpret performance errors. In the study of movements restricted to one joint, the problem of interpreting performance errors is greatly simplified and often overlooked, as performance errors can usually be related to command corrections by a single gain. When multijoint movements of the same motor systems are examined, however, the complex nature of the control and coordination problems faced by the nervous system become evident, as well as the sophistication of the brain's solutions to these problems. Recent progress in the understanding of adaptive control of eye movements provides a good example of this (Berthoz & Melvill-Jones 1985). Experimental studies of the psychophysics of motor learning can play an important role in bridging the gap between computational theories of how abstract motor systems might learn and physiological exploration of how actual nervous systems implement learning. Quantitative analyses of the patterns of motor learning of biological systems may help distinguish alternative hypotheses about the representations used for motor control and learning. What a system can and cannot learn, the amount of generalization, and the rate of learning give clues as to the underlying performance architecture. It is also important to know the actual performance level of the motor system (Loeb 1983). Different proposed control strategies will be able to attain different performance levels, and the use of simplifying control strategies may be evident in the control and learning performance of motor systems.

Arm↗

PubMed2005

Fibril modelling by sequence and structure conservation analysis combined with protein docking techniques: beta(2)-microglobulin amyloidosis.

Obtaining atomic resolution structural models of amyloid fibrils is currently impossible, yet crucial for our understanding of the amyloid mechanism. Different pathways in the transformation of a native globular domain to an amyloid fibril invariably involve domain destabilization. Hence, locating the unstable segments of a domain is important for understanding its amyloidogenic transformation and possibly control it. Since relative conservation is suggested to relate to local stability, we performed an extensive, sequence and structure conservation analysis of the beta(2)-microglobulin (beta(2)-m) domain. Our dataset include 51 high resolution structures belonging to the "C1 set domain" family and 132 clustered PSI-BLAST search results. Segments of the beta(2)-m domain corresponding to strands A (residues 12-18), D (45-55) and G (91-95) were found to be less conserved and stable, while the central strands B (residues 22-28), C (36-41), E (62-70) and F (78-83) were found conserved and stable. Our findings are supported by accumulating observations from various experimental methods, including urea denaturation, limited proteolysis, H/D exchange and structure determination by both NMR and X-ray crystallography. We used our conservation findings together with experimental literature information to suggest a structural model for the polymerized unit of beta(2)-m. Pairwise protein docking and subsequent monomer stacking in the same manner suggest a fibril model consistent with the cross-beta structure.

Amyloid↗

PubMed2006

Issues in multi-item scale testing and development using structural equation models.

Employing a structural equation model to evaluate a measurement scale can be challenging, especially for a multidimensional scale that contains many items. We describe two issues that can contribute to the poor fit of such models: the statistical power associated with the test of a large measurement scale; and the degree of correlation between items and factors within the scale. These issues are not well understood, so our purpose is to explain them at an applied level, clarify their practical implications for tests of measurement scales and other large structural equation models, and discuss potential strategies for addressing them.

Data Interpretation, Statistical↗

PubMed2003

Bayesian model selection for mixtures of structural equation models with an unknown number of components.

This paper considers mixtures of structural equation models with an unknown number of components. A Bayesian model selection approach is developed based on the Bayes factor. A procedure for computing the Bayes factor is developed via path sampling, which has a number of nice features. The key idea is to construct a continuous path linking the competing models; then the Bayes factor can be estimated efficiently via grids in [0, 1] and simulated observations that are generated by the Gibbs sampler from the posterior distribution. Bayesian estimates of the structural parameters, latent variables, as well as other statistics can be produced as by-products. The properties and merits of the proposed procedure are discussed and illustrated by means of a simulation study and a real example.

Bayes Theorem↗

PubMed2005

Modeling for tertiary structure of globin chain in Hemoglobin Suan-Dok disorder.

Hemoglobinopathies are an important inherited disorder with a high prevalence in Southeast Asia. Hemoglobin Suan-Dok is an example of a hemoglobinopathy that was first identified and described in Thailand. It has been identified as an unstable hemoglobin variant associated with alpha-thalassemia. The role of the hemoglobin instability in Hb Suan-Dok in the altered red cell morphology in comparison to the thalassemia-like deficit of alpha globin mRNA has not been entirely resolved and needs additional structural study for clarification. In this study the amino acid sequence of human alpha globin was extracted using ExPASY and compared with that obtained from the Hb Suan-Dok disorder. The derived sequences, alpha globin chains in both the normal and Hb Suan-Dok disorder, were used for further investigation of the tertiary structures. Modeling these proteins for the tertiary structure was performed using the CPHmodels 2.0 Server. For comparison the tertiary structure of human alpha globin chains in normal and hemoglobin Suan-Dok are calculated and presented. Based on this information, there was no significant difference between the predicted alpha globin tertiary structures of normal hemoglobin and Hb Suan-Dok. Therefore, from this study we can state that the tertiary structure of alpha globin is not significantly affected by the mutation in the Hb Suan-Dok disorder and that the effect of this hemoglobin abnormality may be silent. The data suggests that the thalassemic defect associated with the Suan-Dok mutation results from another unidentified process rather than the structural aberration and that the finding of a thalassemic picture might be due to another undetectable inherited hemoglobin disorder.

Hemoglobins, Abnormal↗

PubMed2002

Empirical support for a model of dieting: findings from structural equations modeling.

OBJECTIVE: This paper presents the results of an evaluation of a model of dieting (Huon, G.F., & Strong, K.G., International Journal of Eating Disorders, 23, 361-370, 1998). It represents the culmination of a large-scale time-extended study of dieting among adolescent girls. METHODS: Data were collected from approximately 1,000 girls. A battery of questionnaires assessed dieting status, social influence, vulnerability (conformity) disposition, protective social skills, and aspects of the familial context as core components of the model. RESULTS: When the data were subjected to analyses within structural equations modeling, all specific hypotheses within the model found strong support. Moreover, multiple indices revealed that the model had a very good fit with the data and accounted for 89% of the variance in commitment to dieting. CONCLUSION: This study provides strong support for the validity of Huon and Strong's model of dieting among Australian girls. Its generality among girls in other cultures remains to be established.

Adaptation, Psychological↗

PubMed1997

Molecular modeling of the structures of human and rat pancreatic cholesterol esterases.

Structural models have been generated for rat and human cholesterol esterases by molecular modeling. For rat cholesterol esterase, three separate models were generated according to the following procedure: (1) the cholesterol esterase sequence was aligned with those of three template enzymes: Torpedo californica acetylcholinesterase, Geotrichum candidum lipase and Candida rugosa lipase; (2) the X-ray structure coordinates of the three template enzymes were used to construct cholesterol esterase models by amino acid replacements of matched sequence positions and by making sequence insertions and deletions as required; (3) bad contracts in each of the cholesterol esterase models were relaxed by molecular dynamics and mechanics; (4) the three cholesterol esterase models were merged into one by arithmetic averaging of atomic coordinates; (5) Ramachandran analysis indicated that the model generated from the AChE template possessed the best set of phi/psi angles. Therefore, this model was subjected to molecular dynamics, with harmonic constraints imposed on the C(alpha) coordinates to drive them toward the coordinates of the averaged model. (6) Subsequent relaxation by molecular mechanics produced the final rat cholesterol esterase model. A model for human cholesterol esterase was produced by repeating steps 1-3 above, albeit with the rat cholesterol esterase model as the template. Hydrophobic and electrostatic analyses of the rat and human cholesterol esterase models suggest the structural origins of molecular recognition of hydrophobic substrates and interfaces, of charged interfaces, and of bile salt activators.

Animals↗

PubMed2002

Cross-validation by downweighting influential cases in structural equation modelling.

In the social and behavioural sciences, structural equation modelling has been widely used to test a substantive theory or causal relationship among latent constructs. Cross-validation (CV) is a valuable tool for selecting the best model among competing structural models. Influential cases or outliers are often present in practical data. Therefore, even the correct model for the majority of the data may not cross-validate well. This paper discusses various drawbacks of CV based on sample covariance matrices, and develops a procedure for using robust covariance matrices in the model calibration and validation stages. Examples illustrate that the CV index based on sample covariance matrices is very sensitive to influential cases, and even a single outlier can cause the CV index to support a wrong model. The CV index based on robust covariance matrices is much less sensitive to influential cases and thus leads to a more valid conclusion about the practical value of a model structure.

Behavioral Sciences↗