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DNA structure models deduced from X-ray and physicochemical data for Pfl, Xf, and fd viruses have two antiparallel chains wound in helices of approximately 15 A pitch with the phosphates near the structure axes and the bases directed outward. The models, which differ for each virus, are used to interpret ultraviolet absorbance and fluorescence data in terms of DNA protein interactions.
Plants with specific resistance to a single class of herbicides have been genetically engineered by introduction of genes encoding rationally designed mutant acetohydroxyacid synthase (AHAS) enzymes. Suitable substitution mutations were identified from a three-dimensional model of an AHAS-inhibitor complex. The structural model was generated based on homology to pyruvate oxidase and an imidazolinone inhibitor was positioned in the proposed binding site using structure-activity data for this class of herbicide. Biochemical analysis of the mutant proteins expressed in Escherichia coli enabled iterative optimization of the mutant genes. Expression of recombinant proteins in tobacco plants conferred resistance in vivo. The novel approach coupling molecular modeling and molecular biology has many advantages over traditional random mutagenesis and selection methods and will be crucial to the future development for environmentally safe and sustainable agricultural systems.
The molecular action of lithocholic acid (LCA), a selective inhibitor of mammalian DNA polymerase beta (pol beta), was investigated. We found that LCA could also strongly inhibit the activity of human DNA topoisomerase II (topo II). No other DNA metabolic enzymes tested were affected by LCA. Therefore, LCA should be classified as an inhibitor of both pol beta and topo II. Here, we report the molecular interaction of LCA with pol beta and topo II. By three-dimensional structural model analysis and by comparison with the spatial positioning of specific amino acids binding to LCA on pol beta (Lys60, Leu77, and Thr79), we obtained supplementary information that allowed us to build a structural model of topo II. Modeling analysis revealed that the LCA-interaction interface in both enzymes has a pocket comprised of three amino acids in common, which binds to the LCA molecule. In topo II, the three amino acid residues were Lys720, Leu760, and Thr791. These results suggested that the LCA binding domains of pol beta and topo II are three-dimensionally very similar.
Nearest neighbor relationships between lipid and protein as well as between high-molecular-weight viral RNA and protein were investigated in bovine leukemia virus (BLV) particles using chemical crosslinking reagents. Separation of dimethyl suberimidate (DMS) induced lipid-protein complexes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the phosphoprotein pp 15 is linked to the lipid bilayer of the virus. By use of diepoxybutan (DEB) as crosslinking reagent p 12 and again pp 15 were found to be linked to the viral RNA. Based on these results and our previous data describing the spatial relationships of major structural proteins within BLV particles, a structural model of BLV is proposed.
One hundred and ninety-nine patients and their primary caregivers at two metropolitan cystic fibrosis centers participated in a clinical trial to evaluate the effectiveness of a health education program designed to help improve self-management skills for the care of CF. The baseline data from the study was used to test a structural model that hypothesized the relationship between educational, behavioral, and health status variables. Controlling for the effects of all other variables, including demographic, self-efficacy (confidence in being able to perform a behavior) was the most important educational factor predicting self-management behavior for monitoring and treating respiratory problems. Knowledge about the management of CF was only related to the ability of caretakers to apply coping skills to problems associated with CF. The more caretakers reported performing monitoring behaviors the more likely they were to report performing self-management treatment behaviors. The findings suggest that educational interventions that focus on increased knowledge alone are not likely to be effective in improving self-management behavior for CF. Based on the structural model analyses, it is recommended that educational programs for CF patients and families address increased self-efficacy and improved monitoring skills to influence the improvement of self-management treatment for CF.
Peripheral chlorophyll a/b binding antenna of photosystem I (LHCI) from green algae and higher plants binds specific low energy absorbing chlorophylls (red pigments) that give rise to a unique red-shifted emission. A three-dimensional structural model of the Lhca4 polypeptide from the LHCI from higher plants was constructed on the basis of comparative sequence analysis, secondary structure prediction, and homology modeling using LHCII as a template. The obtained model of Lhca4 helps to visualize protein ligands to nine chlorophylls (Chls) and three potential His residues to extra Chls. Central domain of the Lhca4 comprising the first (A) and the third (C) transmembrane (TM) helices that binds 6 Chl molecules and two carotenoids is conserved structurally, whereas the interface between the first and the second TM helices and the outer surface of the second TM helix differ significantly among the LHCI and LHCII polypeptides. The model of Lhca4 predicts a histidine residue in the second TM helix, a potential binding site for extra Chl in close proximity to Chls a5 and b5 (labeling by Kühlbrandt). The interpigment interactions in the formed pigment cluster are suggested to cause a red spectral shift in absorption and emission. Modeling of the LHCI-730 heterodimer based on the model structures of Lhca1 and Lhca4 allowed us to suggest potential sites of pigment-pigment interactions that might be formed upon heterodimerization or docking of the LHCI dimers to the surface of PSI.
There is a strong case that people construct and manipulate mental models in working memory but relatively little evidence that mental models are preserved in long-term memory. Instead people may remember an episodic construction trace: a record of the operations used to construct a mental model (Payne, 1993). Experiment 1 investigated memory for determinate spatial descriptions (which describe a single configuration of objects) and indeterminate spatial descriptions (which describe two equally plausible configurations). Recognition performance was impaired when the overlap between the episodic construction trace of a description at learning and at test was disrupted by reordering the sentences within a description. Participants were better at remembering the gist of determinate descriptions than that of indeterminate descriptions. For indeterminate descriptions, provided differences in gist recognition were controlled, participants showed better memory for the original description. Experiment 2 showed a similar pattern of results with temporal descriptions. A third experiment manipulated the similarity between foils in the recognition test and the original descriptions to provide further evidence for both episodic construction trace and remembered mental models. In combination, these results favour a hybrid account of memory for mental models, which includes information about both construction processes and model structure.
We present results of structural modeling of the variable fragment of M alpha 2,3, an antibody capable of neutralizing all short snake toxins. Three different methods were used to model the hypervariable loops: the conformational search algorithm CONGEN (Bruccoleri and Karplus, Biopolymers 26:137-168, 1987), high-temperature molecular dynamics (Bruccoleri and Karplus, Biopolymers 29:1847-1862, 1990), and a combined knowledge-based and energy-based algorithm (Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272, 1989). Ninety plausible conformations were generated and were clustered into 13 classes. The clustering results indicate that there was little overlap of the conformational space explored by the different methods. Canonical loop structures were found by all methods for two of the loops, in agreement with previously established empirical modeling criteria. Nine of the 13 classes of structure were rejected on the ground of their lacking common features of antibody combining-site structure. The remaining four models were refined using restrained molecular dynamics. It was found that interconversion between the four resulting structures is possible with no significant energy barriers, suggesting that they are in thermodynamic equilibrium at 300 K. Features of the combining-site structure likely to be particularly important for antigen binding are discussed.
As a basis for direct-methods phasing at very low resolution for macromolecular crystal structures, normalized structure-factor algebra is presented for few-atoms structure models with N = 1, 2, 3, em leader equal atoms or polyatomic globs per unit cell. Main results include: [see text]. Triplet discriminant Delta(hk) and triplet weight W(hk) parameters, a approximately 4.0 and b approximately 3.0, respectively, were determined empirically in numerical error analyses. Tests with phases calculated for few-atoms 'super-glob' models of the protein apo-D-glyceraldehyde-3-phosphate dehydrogenase (approximately 10000 non-H atoms) showed that low-resolution phases from the new few-atoms tangent formula were much better than conventional tangent formula phases for N = 2 and 3; phases from the two formulae were essentially the same for N > or = 4.
PURPOSE: Experimental data suggest that the relative biological effectiveness (RBE) of protons compared to x-rays may be determined by the alpha/beta-ratio of the x-ray survival curve. The data are referring to the centre of a spread-out Bragg peak (SOBP) formed to deliver a homogeneous dose to the tumour by modulating the proton energy. In an effort to explore the basis for this observation, calculations were performed to investigate the response of different biological targets through a range of proton energies and doses. MATERIALS AND METHODS: To describe the x-ray survival curve, the parameters of the linear-quadratic equation, alpha and beta, as well as those of the multi-target/single-hit equation, n and D0, were considered. These parameters were varied to investigate the RBE using the Katz track-structure model. Known cell line characterizations, as well as different hypothetical cells assuming different alpha/beta-ratios but similar target size parameters in the framework of the track-structure theory, were considered. RESULTS: The RBE was found to increase with increasing alpha/beta when the parameter n was varied, but to decrease with increasing alpha/beta when D0 was varied. This held when all other radiosensitivity parameters were assumed to stay constant. Thus, the RBE cannot be predicted by the alpha/beta-ratio alone. CONCLUSIONS: Although there is no direct correlation between the proton RBE and the parameters describing the x-ray survival curve, the track-structure model predicts a tendency for late-responding tissues (low alpha/beta) to have higher RBE values than early-responding tissues (high alpha/beta). These calculations reinforce the experimental findings, but also strongly suggest that there are circumstances in which the tendency for RBE to increase with increasing alpha/beta does not occur, or even could be reversed.
Neurospora VS RNA performs an RNA-mediated self-cleavage reaction whose products contain 2',3'-cyclic phosphate and 5'-hydroxyl termini. This reaction is similar to those of hammerhead, hairpin, and hepatitis delta virus ribozymes; however, VS RNA is not similar in sequence to these other self-cleaving motifs. Here we propose a model for the secondary structure of the self-cleaving region of VS RNA, supported by site-directed mutagenesis and chemical modification structure probing data. The secondary structure of VS RNA is distinct from those of the other naturally occurring RNA self-cleaving domains. In addition to a unique secondary structure, several Mg-dependent interactions occur during the folding of VS RNA into its active tertiary conformation.
We have derived a secondary structure model for the c-myc internal ribosome entry segment (IRES) by using information from chemical probing of the c-myc IRES RNA to constrain structure prediction programs. Our data suggest that the IRES is modular in nature, and can be divided into two structural domains linked by a long unstructured region. Both domains are required for full IRES function. Domain 1 is a complex element that contains a GNNRA apical loop and an overlapping double pseudoknot motif that is topologically unique amongst published RNA structures. Domain 2, the smaller of the two, contains an apical AUUU loop. We have located the ribosome landing site and have shown that ribosomes enter in a 16 nt region downstream of the pseudoknots in a situation similar to that observed in several viral IRESs. To test the structure, several key regions of the IRES were mutated and, interestingly, it appears that some of the structural elements that we have identified function to repress c-myc IRES function. This has profound implications for de-regulation of c-myc expression by mutations occurring in the IRES.
ModBase is a database of evaluated and annotated comparative protein structure models. The database also includes fold assignments and alignments on which the models were based.
The present study is a longitudinal study designed to explore structural relationships between anxiety, depression, personality, and background factors (e.g., gender, age, and complicated medical characteristics) in patients undergoing coronary artery bypass graft (CABG) surgery. At two timepoints before and two after CABG, 217 patients completed self-report questionnaires. To explore structural relationships, the structural equation modeling (SEM) method was applied. Using the model-generating approach, a model was developed, providing a good fit. The structural relationships revealed, in particular, the key position of neuroticism, which was related to both pre- and postoperative anxiety and depression. Relationships between anxiety and depression over time, both intra- and interrelationships, were relatively weak. Relationships between anxiety and depression at the same points in time were relatively strong, with preoperative depression leading to preoperative anxiety, and postoperative anxiety leading to postoperative depression. To provide a useful framework for development of intervention strategies, further research is needed to evaluate the plausibility of the final structural model.
The metal coordination geometries in the structures of the zinc(II) and cobalt(II) complexes of the ligand cis-1,3,5-tris[3-(2-furyl)prop-2-enylideneamino]cyclohexane (fr-protach) and with the anions nitrate and acetate are structural models for the active site of carbonic anhydrase. The acetate structures show a striking structural correlation with the metal coordination environments in the known bicarbonate forms of the enzyme. Such structures provide a basis for understanding the marked effect of different metal substitution on the catalytic rate of the enzyme.
The 4 A X-ray structure model of trimeric photosystem I of the cyanobacterium Synechococcus elongatus reveals 31 transmembrane, nine surface and three stromal alpha-helices per monomer, assigned to the 11 protein subunits: PsaA and PsaB are related by a pseudo two-fold axis normal to the membrane plane, along which the electron transfer pigments are arranged. 65 antenna chlorophyll a (Chl a) molecules separated by < or = 16 A form an oval, clustered net continuous with the electron transfer chain through the second and third Chl a pairs of the electron transfer system. This suggests a dual role for these Chl a both in excitation energy and electron transfer. The architecture of the protein core indicates quinone and iron-sulphur type reaction centres to have a common ancestor.
A conceptual model of work-school conflict was developed and tested. This study extends prior adolescent employment research by investigating the process by which job characteristics are associated with school outcomes. Data were obtained from a sample of 319 adolescents (16 to 19 years old) who were full-time students and part-time workers. The model was tested using structural equation modeling techniques. Results supported the hypothesized path model. Job characteristics (workload, number of work hours, and job dissatisfaction) were positively related to work-school conflict. Work-school conflict was negatively related to school readiness. School readiness was positively related to school performance, which was negatively associated with school dissatisfaction. In addition, results support a feedback relation, such that school dissatisfaction is negatively related to school readiness.
Macrophage inflammatory protein 1 alpha (MIP-1 alpha), a monocyte cytokine, has roles postulated for it in neutrophil chemoattraction, the inflammatory response and the control of haemopoietic stem cell proliferation. The three-dimensional structure of MIP-1 alpha has been modelled structurally, based on its sequence similarity to interleukin-8 and related proteins. The predicted dimeric form of MIP-1 alpha contains two symmetry-related antiparallel alpha-helices lying at an angle across a beta-sheet. The interhelical region and the beta-sheet flooring it are discussed as the potential receptor-binding site in terms of the distribution of negatively charged amino-acid side-chains, which contrasts remarkably with the corresponding positively-charged locations for IL-8. The general topographical features of this (alpha + beta) structural family of cytokines and related proteins (including HLA-A2, PF-4) are discussed. The members of this cytokine family fall into two structural groups as the antiparallel helices (N to C directed) mounted across the beta-sheet platform can be located in a clockwise (e.g. HLA-A2) or anticlockwise (e.g. MIP-1 alpha) sense with respect to the beta-floor).