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At least 127 records · Page 7Linked to original sources

PubMed1994

Mutational analysis supports a structural model for the cell cycle protein kinase p34.

Structural models for the eukaryotic cell cycle control protein p34 from human, S. pombe and S. cerevisiae have been derived from the crystallographic coordinates of the cAMP-dependent protein kinase (cAPK) catalytic subunit (active conformation) and compared with the structure of inactive CDK2 apoenzyme. Differences between the p34 and cAPK catalytic sites provide a possible explanation for their different substrate specificities. The p34 models localize Tyr15 and Thr14 close to the sites of catalysis and substrate recognition where their phosphorylation could inhibit p34 kinase activity either by blocking MgATP or substrate binding. The conserved sequences PSTAIRE and LYLIFEFL are both close to the catalytic site and accessible on the protein surface available to mediate interactions with other proteins. It is predicted that p34 has an active-site cleft composed almost entirely of sequences common to all protein kinases and sequences unique to the p34 protein family. Genetic and biochemical analyses of p34 have shown that it interacts extensively with a number of other proteins. The model allows the relative disposition of these sites of mutation to each other and to the sites of catalysis and substrate recognition to be appreciated. Surface regions on p34 that are important for function have been identified. These sites identify residues that may interact with p13suc1, cyclin, p107wee1 and p80cdc25.

Amino Acid Sequence↗

PubMed1997

Development of a cancellous bone structural model by stereolithography for ultrasound characterisation of the calcaneus.

A novel method for the development of a user-defined structural model simulating cancellous bone of the human calcaneus is described using stereolithography (SL). The digital image of a cancellous bone section was modified by skeletonisation and dilation to produce a structural model of uniform wall thickness, determined by the resolution of the stereolithography system. Six SL models were produced using the same data file. The SL models were assessed using the McCue CUBAclinical ultrasound bone densitometer. The broadband ultrasound attenuation (BUA) and velocity (VOS) values obtained were commensurate with the commercial phantom provided with the CUBAclinical system. The intra- and inter-sample variability for the six SL models were similar at 5% for BUA and 2.5% for VOS. Stereolithography offers the potential to firstly, simulate perforation and thinning of cancellous bone associated with osteoporosis, and secondly, to evaluate the dependence of ultrasonic and mechanical parameters upon cancellous bone structure.

Anisotropy↗

PubMed1998

Structural model for family 32 of glycosyl-hydrolase enzymes.

A structural model is presented for family 32 of the glycosyl-hydrolase enzymes based on the beta-propeller fold. The model is derived from the common prediction of two different threading methods, TOPITS and THREADER. In addition, we used a correlated mutation analysis and prediction of active-site residues to corroborate the proposed model. Physical techniques (circular dichroism and differential scanning calorimetry) confirmed two aspects of the prediction, the proposed all-beta fold and the multi-domain structure. The most reliable three-dimensional model was obtained using the structure of neuraminidase (1nscA) as template. The analysis of the position of the active site residues in this model is compatible with the catalytic mechanism proposed by Reddy and Maley (J. Biol. Chem. 271:13953-13958, 1996), which includes three conserved residues, Asp, Glu, and Cys. Based on this analysis, we propose the participation of one more conserved residue (Asp 162) in the catalytic mechanism. The model will facilitate further studies of the physical and biochemical characteristics of family 32 of the glycosyl-hydrolases.

Amino Acid Sequence↗

PubMedDate not supplied

A simple structured model describing the growth of Streptomyces lividans.

The growth of Streptomyces lividans in defined media was modeled using a simple structured growth model. Conventional unstructured models like Monod kinetics, substrate inhibition kinetics, and the logistic equation were also used in an attempt to fit the data, but the results were all unsatisfactory. The main reason for failure in applying simple unstructured models is that they cannot describe the long lag phases sometimes observed during growth of S. lividans. The simple structured growth model was derived along similar principles to cybernetic growth models. This model quite accurately describes the growth of S. lividans. It assumes that the rate of assimilation of a substrate depends on the concentration of a specific key enzyme. This key enzyme is only produced in the presence of the substrate, and it is broken down at a steady rate. An enzyme synthesis allocation variable, w, similar to the cybernetic variable, u, described in cybernetic growth models, is proposed to control enzyme synthesis. Until the key enzyme concentration approaches its maximum level, very little substrate is consumed. And consequently, the lag phase is sustained.

Models, Biological↗

PubMed1984

A structural model of the acetylcholine receptor channel based on partition energy and helix packing calculations.

A structural model of the transmembrane portion of the acetylcholine receptor was developed from sequences of all its subunits by using transfer energy calculations to locate transmembrane alpha-helices and to calculate which helical side chains should be in contact with water inside the channel, with portions of other transmembrane helices, or with lipid hydrocarbon chains. "Knobs-into-holes" side chain packing calculations were used with other factors to stack the transmembrane alpha-helices together. In the model each subunit has the following structures in order along the sequence from the NH2 terminus: a large extracellular domain of undetermined structure, a short apolar alpha-helix that lies on the extracellular lipid surface of the membrane; three apolar transmembrane alpha-helices (I, II, and III), a cytoplasmic domain of undetermined structure, an amphipathic transmembrane alpha-helix (L) that forms the channel lining, a short extracellular alpha-helix, another apolar transmembrane alpha-helix (IV), and a small cytoplasmic domain formed by the COOH-terminal end of the chain. Three concentric layers form the pore. A bundle of five amphipathic L helices forms the channel lining. This bundle is surrounded by a bundle of 10 alternating II and III helices. Helices I and IV cover portions of the outer surface of the bundle formed by helices II and III. Positions of disulfide bridges are predicted and a mechanism for opening and closing conformational changes is proposed that requires tilting transmembrane helices and possibly a thiol-disulfide interchange reaction.

Amino Acid Sequence↗

PubMed1999

Dimorphism of polyglycine I: structural models for crystal modifications.

Re-examination of the known data on crystalline forms of polyglycine reveals that the crystal modification 'polyglycine I' has two different three-dimensional structures depending on the molecular weight. Structural models for both low molecular weight (LMW) and high molecular weight (HMW) polyglycine I crystals are described. In the LMW crystal model, the molecules have an unusual extended conformation generated by alternation of two mirror-symmetrical residual conformations along the chain. The molecules are parallel and each chain forms interpeptide hydrogen bonds with four adjacent chains. The structural model for the HMW crystal represents a composition of twinning crystallites. The crystallites themselves consist of antiparallel enantiomorphous chains united by hydrogen bonds to form rippled sheets. Calculations of the diffraction patterns and packing energy show that these polyglycine I structures have a higher level of conformity with the experimental data than previously suggested models. New insight into the structure of the polyglycine associates opens up the possibility of designing improved silk-like and nylon materials.

Crystallography, X-Ray↗

PubMed1994

Structure from function: screening structural models with functional data.

Structural constraints derived from different antibody epitopes on human growth hormone (hGH) were used to screen three-dimensional models of hGH that were generated by computer algorithms. Previously, alanine-scanning mutagenesis defined the residues that modulate binding to 21 different monoclonal antibodies to hGH. These functional epitopes were composed of 4-14 side chains whose alpha-carbons clustered within 4-23 A. Distance and topographic constraints for these functional epitopes were virtually the same as constraints derived from known x-ray structures of protein-antigen complexes. The constraints were used to evaluate about 1400 models of hGH that were computer-generated by a secondary-structure prediction and packing algorithm. On average each functional epitope reduced the number of models in the pool by a factor of 2, so that 8 monoclonal antibodies could reduce the number of possible models to < 10. The average root-mean-square deviation of alpha-carbon coordinates between the x-ray structure and either the pool of starting models or final models ranged from 13 to 16 A or 4 to 7 A, respectively, depending on the pool of starting models and the level of constraints imposed. All of the final models had the correct folding topography, and the best model was within 3.8 A root-mean-square deviation of the x-ray coordinates. This model was as close as it could have been because the models were built by using ideal helices and those in the x-ray structure are not. Our studies suggest that epitope mapping data can effectively screen structural models and, when coupled to predictive algorithms, can help to generate low-resolution models of a protein.

Amino Acid Sequence↗

PubMed1995

Secondary structure model of the Mason-Pfizer monkey virus 5' leader sequence: identification of a structural motif common to a variety of retroviruses.

A stable secondary structure model is presented for the region 3' of the primer-binding site to 130 bases into the gag sequence of the prototype type D retrovirus Mason-Pfizer monkey virus. Using biochemical probing of RNA from this region in association with free energy minimization, we have identified a stem-loop structure in the region, which from other studies has been shown to be important for genomic RNA encapsidation. The structure involves a highly stable stem of five G-C pairs terminating in a heptaloop. Comparison of the Mason-Pfizer monkey virus structure with one predicted for squirrel monkey retrovirus demonstrates an identical stem and a common ACC motif in the loop. Free energy studies of the secondary structure of the 5' regions of eight other retroviruses predict stem loops which have similar GAYC motifs. We believe this may represent a common structural and sequence motif which among other functions may be involved in genomic RNA packaging in these viruses.

Animals↗

PubMed1994

A secondary structure model of the integrin alpha subunit N-terminal domain based on analysis of multiple alignments.

The integrins are alpha/beta heterodimeric proteins which mediate cell-matrix and cell-cell interactions. Current data indicate that the N-terminal moiety of the alpha subunit is involved in ligand binding. This region of the receptor is made up of a seven-fold repeated sequence of unknown structure which contains EF-hand-like putative divalent cation-binding sites. Recent studies have shown that multiple sequence alignments can be analysed to yield secondary structure predictions. Therefore, to obtain a model structure for the integrin alpha subunit N-terminal domain repeat, a large alignment of the seven repeats from sixteen integrin sequences was generated. Two methods of analysis were used: First, Chou and Fasman and Garnier, Osguthorpe and Robson predictions were carried out for individual sequences and the consensus predictions derived. Consensus hydrophobicity and chain flexibility data were also used to provide additional data. Second, sites of conservation and variation were analysed by a computer program STAMA (STructure After Multiple Alignment) to yield a secondary structure prediction. The two analyses gave essentially the same predicted structure: undefined region, loop, alpha-helix, beta-strand, divalent cation-binding loop, beta-strand, putative turn, loop, beta-strand. This is the first model structure to be presented for an integrin domain. Its implications for integrin function are discussed.

Amino Acid Sequence↗

PubMed1996

Structural model of the outer vestibule and selectivity filter of the Shaker voltage-gated K+ channel.

A new generation of structural models were developed of the outer vestibule and ion-selective portion of the voltage-gated Shaker K+ channel. Some features of these models are similar to those that we have developed previously [Durrel S. R. and Guy H. R. (1992) Biophys. J. 62, 238-250; Guy H. R. (1990) In Monovalent Cations in Biological Systems (Pasternak C. A., Ed.), pp. 31-58, CRC Press, Boca Raton, FL; Guy H. R. and Durell S. R. (1994) In Molecular Evolution of Physiological processes (Fambrough D., Ed.), pp. 197-212, The Rockefeller University Press, NY; Guy H. R. and Durell S. R. (1995) In Ion Channels and Genetic Diseases (Dawson D., Ed.), pp. 1-16, The Rockefeller University Press, NY] and other features were modified to make the models more consistent with recent experimental findings. The first part of the P segment is postulated, as always, to form a short alpha helix that spans only the outer portion of the membrane. The helix is tilted so that its C-terminal is nearer the pore than its N-terminal. The latter part of the P segment, P2, is postulated to have a relatively elongated conformation that is positioned approximately parallel to the axis of the pore. Four of the P2 segments assemble to form an ion-selective region that has two narrow regions; one formed by the Y445 side-chains at the outer entrance of the pore and one formed by the backbone of the T442 residues near the innermost part of the P segments. The S6 segment is postulated to form two alpha helices. The first S6 helix packs next to the P segments in our models. The NMR structures of two scorpion toxins, charybdotoxin and agitoxin 2, have been docked into the models of the outer vestibules. The shape of the outer vestibule has been modeled so that specific toxin-channel residue-residue interactions correspond to those that have been identified experimentally.

4-Aminopyridine↗

PubMed1996

Structural model for the selenocysteine-specific elongation factor SelB.

A structural model was established for the N-terminal part of translation factor SelB which shares sequence similarity with EF-Tu, taking into account the coordinates of the EF-Tu 3D structure and the consensus of SelB sequences from four bacteria. The model showed that SelB is homologous in its N-terminal domains over all three domains of EF-Tu. The guanine nucleotide binding site and the residues involved in GTP hydrolysis are similar to those of EF-Tu, but with some subtle differences possibly responsible for the higher affinity of SelB for GTP compared to GDP. In accordance, the EF-Tu epitopes interacting with EF-Ts are lacking in SelB. Information on the formation of the selenocysteyl-binding pocket is presented. A phylogenetic comparison of the SelB domains homologous to EF-Tu with those from EF-Tu and initiation factor 2 indicated that SelB forms a separate class of translation factors.

Amino Acid Sequence↗

PubMed1999

Genetically structured modeling of protein production in filamentous fungi.

A general framework for a genetically structured model is presented. The framework allows description of the interactions in a system of regulatory and structural genes. The model assumes equilibrium kinetics for the binding of regulatory proteins to the promoter regions of the genes and includes the possible activation of proteins following their synthesis. The model is evaluated by simulating the alcA-expression (alcohol dehydrogenase I) in Aspergillus nidulans which is an inducible system subject to glucose repression. The intracellular enzyme levels in strains with different regulatory mutations are simulated during various growth conditions. The model gives a good description of the experimental data with changes in only a few parameter values which have a mechanistic interpretation.

Alcohol Dehydrogenase↗

PubMed1991

A three-dimensional motion model of loads on the lumbar spine: I. Model structure.

Traditionally most biomechanical models that are used to estimate the loading experienced by the spine during work focus on static, two-dimensional representations of the work. However, most work tasks impose loads on the lumbar spine under dynamic, three-dimensional conditions. The objective of this study was to describe the structure and logic of a model that is capable of producing estimates of spine loading under three-dimensional motion conditions. This model is intended for use primarily under laboratory conditions. The model was designed initially for workplace simulation in which the trunk is moving under symmetric and asymmetric constant velocity lifting conditions. Future embellishments may enable the model to be used under free dynamic conditions. The model predicts lumbar spine compression, shear, and torsional forces as well as trunk torque production continuously throughout the exertion. This information may be compared with spine tolerance limits so that the risk of causing a vertebral end-plate microfracture by workplace requirements could be determined.

Biomechanical Phenomena↗

PubMed1992

Structural models for the metal centers in the nitrogenase molybdenum-iron protein.

Structural models for the nitrogenase FeMo-cofactor and P-clusters are proposed based on crystallographic analysis of the nitrogenase molybdenum-iron (MoFe)-protein from Azotobacter vinelandii at 2.7 angstrom resolution. Each center consists of two bridged clusters; the FeMo-cofactor has 4Fe:3S and 1Mo:3Fe:3S clusters bridged by three non-protein ligands, and the P-clusters contain two 4Fe:4S clusters bridged by two cysteine thiol ligands. Six of the seven Fe sites in the FeMo-cofactor appear to have trigonal coordination geometry, including one ligand provided by a bridging group. The remaining Fe site has tetrahedral geometry and is liganded to the side chain of Cys alpha 275. The Mo site exhibits approximate octahedral coordination geometry and is liganded by three sulfurs in the cofactor, two oxygens from homocitrate, and the imidazole side chain of His alpha 442. The P-clusters are liganded by six cysteine thiol groups, two which bridge the two clusters, alpha 88 and beta 95, and four which singly coordinate the remaining Fe sites, alpha 62, alpha 154, beta 70, and beta 153. The side chain of Ser beta 188 may also coordinate one iron. The polypeptide folds of the homologous alpha and beta subunits surrounding the P-clusters are approximately related by a twofold rotation that may be utilized in the binding interactions between the MoFe-protein and the nitrogenase Fe-protein. Neither the FeMo-cofactor nor the P-clusters are exposed to the surface, suggesting that substrate entry, electron transfer, and product release must involve a carefully regulated sequence of interactions between the MoFe-protein and Fe-protein of nitrogenase.

Azotobacter vinelandii↗

PubMed1993

The use of causal indicators in covariance structure models: some practical issues.

In conventional representations of covariance structure models, indicators are defined as linear functions of latent variables, plus error. In an alternative representation, constructs can be defined as linear functions of their indicators, called causal indicators, plus an error term. Such constructs are not latent variables but composite variables, and they have no indicators in the conventional sense. The presence of composite variables in a model can, in some situations, result in problems with identification of model parameters. Also, the use of causal indicators can produce models that imply zero correlation among many measured variables, a problem resolved only by the inclusion of a potentially large number of additional parameters. These phenomena are demonstrated with an example, and general principles underlying them are discussed. Remedies are described so as to allow for the evaluation of models that contain causal indicators.

Analysis of Variance↗

PubMed1982

Sequences of three molluscan 5 S ribosomal RNAs confirm the validity of a dynamic secondary structure model.

The collection of known 5 S rRNA primary structures is enriched with the sequences from three mollusca, the snails Helix pomatia and Arion rufus, and the mussel Mytilus edulis. The three sequences can be fitted in a five-helix secondary structure model previously shown (De Wachter et al. (1982) Biochimie 64, 311-329) to apply to all 5 S RNAs regardless of their origin. One of the helices in this model can undergo a bulge-internal loop transition. Within the metazoan kingdom, the dimensions of each helix and loop are rigidly conserved, except for one helix which can comprise either 6 or 7 base pairs.

Animals↗

PubMed1999

A physiological model for tert-amyl methyl ether and tert-amyl alcohol: hypothesis testing of model structures.

The oxygenate tert-amyl methyl ether (TAME) is a gasoline fuel additive used to reduce carbon monoxide in automobile emissions. To evaluate the relative health risk of TAME as a gasoline additive, information is needed on its pharmacokinetics and toxicity. The objective of this study was to use a physiologically-based pharmacokinetic (PBPK) model to describe the disposition of TAME and its major metabolite, tert-amyl alcohol (TAA), in male Fischer-344 rats. The model compartments for TAME and TAA were flow-limited. The TAME physiological model had 6 compartments: lung, liver, rapidly perfused tissues, slowly perfused tissues, fat, and kidney. The TAA model had 3 compartments: lung, liver, and total-body water. The 2 models were linked through metabolism of TAME to TAA in the liver. Model simulations were compared with data on blood concentrations of TAME and TAA taken from male Fischer-344 rats during and after a 6-hour inhalation exposure to 2500, 500, or 100 ppm TAME. The PBPK model predicted TAME pharmacokinetics when 2 saturable pathways for TAME oxidation were included. The TAA model, which included pathways for oxidation and glucuronide conjugation of TAA, underpredicted the experimental data collected at later times postexposure. To account for biological processes occurring during this time, three hypotheses were developed: nonspecific binding of TAA, diffusion-limited transport of TAA, and enterohepatic circulation of TAA glucuronide. These hypotheses were tested using three different model structures. Visual inspection and statistical evaluation involving maximum likelihood techniques indicated that the model incorporating nonspecific binding of TAA provided the best fit to the data. A correct model structure, based upon experimental data, statistical analyses, and biological interpretation, will allow a more accurate extrapolation to humans and, consequently, a greater understanding of human risk from exposure to TAME.

Administration, Inhalation↗

PubMed2000

A structural model of the orthorhombic Ga7Mn5 derived from its HREM image

The base-centered orthorhombic approximant Ga7Mn5 (a = 4.547(6) nm, b = 1.256(9) nm, c = 1.482(1) nm) consisting of flattened hexagon and concave octagon (called "crown" in this paper) subunits shown by high-resolution electron microscopy (HREM) was found to coexist with the Ga-Mn decagonal quasicrystal in the Ga58Mn42 alloy. The atomic sites in the flattened hexagon subunit have been deduced recently from a structural study of the orthorhombic Ga-Mn (1/1,1/1) approximant that consists only of the hexagon subunits. Similarly, the atomic sites in the crown subunit have been deduced from another orthorhombic Ga-Mn (2/1,1/1) approximant consisting only of the crown subunits. A structural model of the orthorhombic Ga7Mn5 can thus be constructed from these structural subunits. There are 332 Ga atoms and 232 Mn atoms in a unit cell, with a composition of Mn41.2Ga58.8, satisfying the symmetry of the space group Bmm2. The simulated electron diffraction patterns, [010] HREM images, and X-ray powder diffraction pattern based on this structural model agrees mainly with the experimental observations.

Journal Article↗