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Results for “Models, Structural”

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At least 703 records · Page 39Linked to original sources

PubMed1998

Differential chemical probing of a group II self-splicing intron identifies bases involved in tertiary interactions and supports an alternative secondary structure model of domain V.

Dimethyl sulfate modification was used to probe for tertiary structural elements in the group II intron PI.LSU/2 from the mitochondrial pre-ribosomal RNA of the brown alga Pylaiella littoralis. Modification of the lariat form of the intron under conditions that allow both native folding and conformational homogeneity is found to be generally consistent with secondary and tertiary structural features identified previously for group II ribozymes. A comparison of chemical probing at temperatures just below and above the first melting transition illustrates the cooperative unfolding of tertiary structure and identifies novel candidates for tertiary interactions in addition to defining elements of secondary structure. Substitution of the GAAA terminal loop of domain V is shown to be compatible with retention of conformational homogeneity (despite the loss of an important tertiary interaction), but produces a concise methylation footprint in domain I at the site previously shown to harbor the receptor for that loop. The analysis also identified two nucleotide positions in domain V with novel secondary and potential tertiary structural roles. The proposed refinement of domain V secondary structure is supported by an expanded comparative analysis of group II sequences and bears increased resemblance to U2:U6 snRNA pairing in the spliceosome.

Alkylating Agents↗

PubMed2000

Structural model of F1-ATPase and the implications for rotary catalysis.

The crystal structure of bovine mitochondrial F1-ATPase is described. Several features of the structure are consistent with the binding change mechanism of catalysis, in which binding of substrates induces conformational changes that result in a high degree of cooperativity between the three catalytic sites. Furthermore, the structure also suggests that catalysis is accompanied by a physical rotation of the centrally placed gamma-subunit relative to the approximately spherical alpha3beta3 subassembly.

Animals↗

PubMed1995

Structural model of the photosynthetic reaction center of Rhodobacter capsulatus.

The reaction center (RC) from the photosynthetic bacterium Rhodobacter (Rb.) capsulatus has been the subject of a considerable amount of molecular biological and spectroscopic work aimed at improving our understanding of the primary steps of photosynthesis. However, no three-dimensional structure is available for this protein. We present here a model obtained by combining information from the structure of the highly homologous RC from Rhodopseudomonas (Rps.) viridis with molecular mechanics and simulated annealing calculations. In the Rb. capsulatus model the orientations of the bacteriochlorophyll monomer and the bacteriopheophytin on the branch inactive in electron transfer differ significantly from those in the RCs of Rps. viridis and Rb. sphaeroides. The bacteriopheophytin orientational difference is in good accord with previous linear dichroism measurements. A comparison is made of interactions between the pigments and the protein environment that may be of functional significance in Rps. viridis, Rb. sphaeroides, and Rb. capsulatus.

Amino Acids↗

PubMed2006

Comparison of factor structure models for the Beck Depression Inventory--II.

Factor analyses of the Beck Depression Inventory--II (A. T. Beck, R. A. Steer, & G. K. Brown, 1996) have frequently produced 2 different 2-factor oblique structures. The author used confirmatory factor analyses to compare these structures with a general-factor model with 2 orthogonal group factors. The general-factor model fit as well as or better than the 2-factor models when applied to item data from previous studies (3 clinical and 2 college samples). Communalities associated with the General Depression factor ranged from 71% to 82%. Cognitive and Somatic group factors were indicative of intropunitiveness and fatigue. It was concluded that the general-factor model gives an acceptable empirical explanation of item covariance structure and offers a conceptual interpretation that is well suited to clinical practice and research.

Adult↗

PubMed1990

Protein model structure evaluation using the solvation free energy of folding.

A systematic study of solvation free energy of folding for proteins with known crystallographic structures is presented. There is a linear relationship between the solvation free energy of folding and the protein size. This relationship, which can be rationalized by a simple model of chain folding, allows prediction of the solvation free energy of folding for proteins for which no high resolution structures are available. All misfolded structures analyzed show solvation free energies higher than predicted; however, some of the misfolded structures have values close enough to the predicted values so that one must be very careful when using such a criterion to check the correctness of a protein model.

Enzymes↗

PubMed2006

Structure modeling, ligand binding, and binding affinity calculation (LR-MM-PBSA) of human heparanase for inhibition and drug design.

Human heparanase is an endo-beta-D-glycosidase that cleaves heparan sulphate (HS) chains in the extracellular matrix and basement membrane. It is known that the cleavage of HS by heparanase results in cell invasion and metastasis of cancer. Therefore, heparanase is considered an important target for cancer drug development. The three-dimensional structure of heparanase would be useful in the rational design of inhibitors targeted to the enzyme; however, the three-dimensional structure has not yet been determined. In our effort to design inhibitors, we developed a three-dimensional structure of heparanase using a homology-modeling approach. The homology-built structure is consistent to previous bioinformatics and site-mutation experimental results. The heparanase features a (alpha/beta)(8) TIM-barrel fold with two glutamate residues (Glu225 and Glu343) located in the active-site cleft. This feature supports the putative mechanism of proton donor and nucleophilic sites. Docking simulations yielded 41 complex structures, which indicate that the bound inhibitor could block ligand binding into the catalytic site. A free energy of binding model was established for 25 heparanase inhibitors with a training set of 25 heparanase inhibitors using the linear response MM-PBSA approach (LR-MM-PBSA). The correlation between calculated and experimental activity was 0.79 and the reliability of the model was validated with leave-one-out cross-validation method. Its predictive capability was further validated using a test set of 16 inhibitors similar to the training set of inhibitors. The correlation between the predicted and observed activities is significantly improved by the protein "induced-fit" that accounts for the flexibility of the receptor. These interaction and pharmacophore elements provide a unique insight to the rational design of new ligands targeted to the enzyme.

Amino Acid Sequence↗

PubMed1978

Protected homo-oligopeptide structure: Model for preferred conformation of a linear methionine heptapeptide in chloroform.

The (1)H nuclear magnetic resonance spectra for a protected linear heptapeptide of methionine, Boc-Met(7)-OMe, were measured in dimethyl-d(6) sulfoxide and C(2)HCl(3) solutions. In the former, the peptide is disordered. In C(2)HCl(3), preferred (short-range) interactions exist that dominate the overall secondary structure of the peptide. A model is proposed in which seven-membered ring structures are initiated at the NH(2)-terminus and propagate toward the carboxyl terminus. The first seven-membered ring contains a strong hydrogen bond between the amide NH of residue 2 and the carbonyl oxygen atom of the urethane blocking group. As one proceeds toward the carboxyl terminus the hydrogen bond strength of succeeding rings decreases, and at residue 5 the peptide chain assumes an extended structure that is stabilized by intermolecular hydrogen bonds. The model accounts for most of the results from (1)H NMR and infrared studies on the heptapeptide and is consistent with conformational energy calculations on homo-oligopeptides. It suggests that the COOH-terminal residues may serve as the nucleus for intermolecular peptide-peptide associations.

Journal Article↗

PubMed1990

Hemoglobin Saint Mandé [beta 102 (G4) Asn----Tyr]. Functional studies and structural modeling reveal an altered T state.

Oxygen equilibrium studies of purified hemoglobin Saint Mandé (Hb SM) [beta 102 (G4) Asn----Tyr] reveal a decreased oxygen affinity and cooperativity but to a lesser extent than found for Hb Kansas (beta 102 Thr). The low affinity of Hb SM depends on environmental conditions: eliminating chloride or raising the pH greatly elevated the ratio of p50 of Hb SM to that of Hb A. The alkaline Bohr effect is reduced by about 40%. The effects of anions (chloride, organophosphates) binding to deoxy Hb SM are also reduced. These data indicate that the functional properties of Hb SM are intermediary between Hb A and Hb Kansas. In addition, molecular graphics modeling of Hb SM in the oxy and deoxy structures indicate the possibility of a new hydrogen bond in the T state between beta(1)102 Tyr and alpha(2)42 Tyr. Stabilisation of the T state in this manner is a plausible explanation for several of the effects observed.

Asparagine↗

PubMed2004

A framework for structured modeling of skeletal muscle.

The aim of this study is to present a detailed continuum mechanics formulation, and the corresponding algorithms, to predict the deformation of skeletal muscle at different structural levels, starting from the muscle fiber level. The model is used to investigate force production and structural changes during isometric and dynamic contractions of the cat medial gastrocnemius. From a comparison with experimental data obtained in our own laboratories, we conclude that the model faithfully predicts all of the observations pertaining to force production, fascicle length and angle of pennation under various test conditions.

Algorithms↗

PubMed2004

Consensus structural models for the amino terminal domain of the retrovirus restriction gene Fv1 and the murine leukaemia virus capsid proteins.

BACKGROUND: The mouse Fv1 (friend virus) susceptibility gene inhibits the development of the murine leukaemia virus (MLV) by interacting with its capsid (CA) protein. As no structures are available for these proteins we have constructed molecular models based on distant sequence similarity to other retroviral capsid proteins. RESULTS: Molecular models were constructed for the amino terminal domains of the probable capsid-like structure for the mouse Fv1 gene product and the capsid protein of the MLV. The models were based on sequence alignments with a variety of other retrovirus capsid proteins. As the sequence similarity of these proteins with MLV and especially Fv1 is very distant, a threading method was employed that incorporates predicted secondary structure and multiple sequence information. The resulting models were compared with equivalent models constructed using the sequences of the capsid proteins of known structure. CONCLUSIONS: These comparisons suggested that the MLV model should be accurate in the core but with significant uncertainty in the loop regions. The Fv1 model may have some additional errors in the core packing of its helices but the resulting model gave some support to the hypothesis that it adopts a capsid-like structure.

Amino Acid Sequence↗

PubMed1990

A dynamic growth model of vegetative soya bean plants: model structure and behaviour under varying root temperature and nitrogen concentration.

A differential equation model of vegetative growth of the soya bean plant (Glycine max (L.) Merrill cv. Ransom') was developed to account for plant growth in a phytotron system under variation of root temperature and nitrogen concentration in nutrient solution. The model was tested by comparing model outputs with data from four different experiments. Model predictions agreed fairly well with measured plant performance over a wide range of root temperatures and over a range of nitrogen concentrations in nutrient solution between 0.5 and 10.0 mmol NO3- in the phytotron environment. Sensitivity analyses revealed that the model was most sensitive to changes in parameters relating to carbohydrate concentration in the plant and nitrogen uptake rate.

Carbohydrate Metabolism↗

PubMed2004

Selectively receptor-blind measles viruses: Identification of residues necessary for SLAM- or CD46-induced fusion and their localization on a new hemagglutinin structural model.

Measles virus (MV) enters cells either through the signaling lymphocyte activation molecule SLAM (CD150) expressed only in immune cells or through the ubiquitously expressed regulator of complement activation, CD46. To identify residues on the attachment protein hemagglutinin (H) essential for fusion support through either receptor, we devised a strategy based on analysis of morbillivirus H-protein sequences, iterative cycles of mutant protein production followed by receptor-based functional assays, and a novel MV H three-dimensional model. This model uses the Newcastle disease virus hemagglutinin-neuraminidase protein structure as a template. We identified seven amino acids important for SLAM- and nine for CD46 (Vero cell receptor)-induced fusion. The MV H three-dimensional model suggests (i) that SLAM- and CD46-relevant residues are located in contiguous areas in propeller beta-sheets 5 and 4, respectively; (ii) that two clusters of SLAM-relevant residues exist and that they are accessible for receptor contact; and (iii) that several CD46-relevant amino acids may be shielded from direct receptor contacts. It appears likely that certain residues support receptor-specific H-protein conformational changes. To verify the importance of the H residues identified with the cell-cell fusion assays for virus entry into cells, we transferred the relevant mutations into genomic MV cDNAs. Indeed, we were able to recover recombinant viruses, and we showed that these replicate selectively in cells expressing SLAM or CD46. Selectively receptor-blind viruses will be used to study MV pathogenesis and may have applications for the production of novel vaccines and therapeutics.

Amino Acid Sequence↗

PubMed2005

Assembly of lipoprotein particles containing apolipoprotein-B: structural model for the nascent lipoprotein particle.

Apolipoprotein B (apoB) is the major protein component of large lipoprotein particles that transport lipids and cholesterol. We have developed a detailed model of the first 1000 residues of apoB using standard sequence alignment programs (ClustalW and MACAW) and the MODELLER6 package for three-dimensional homology modeling. The validity of the apoB model was supported by conservation of disulfide bonds, location of all proline residues in turns and loops, and conservation of the hydrophobic faces of the two C-terminal amphipathic beta-sheets, betaA (residues 600-763) and betaB (residues 780-1000). This model suggests a lipid-pocket mechanism for initiation of lipoprotein particle assembly. In a previous model we suggested that microsomal triglyceride transfer protein might play a structural role in completion of the lipid pocket. We no longer think this likely, but instead propose a hairpin-bridge mechanism for lipid pocket completion. Salt-bridges between four tandem charged residues (717-720) in the turn of the hairpin-bridge and four tandem complementary residues (997-1000) at the C-terminus of the model lock the bridge in the closed position, enabling the deposition of an asymmetric bilayer within the lipid pocket.

Amino Acid Sequence↗

PubMed2001

Mass spectrometric evaluation of synthetic peptides as primary structure models for peptide and protein deamidation.

Solid-phase peptide synthesis and deamidation measurements using a novel mass spectrometric technique were carried out for 94 model asparaginyl peptides from 3 to 13 residues in length. Deamidation rates of these peptides in pH 7.4, 37.0 degrees C, 0.15 M Tris-HCl buffer were measured and evaluated. It was found that they validate the use of pentapeptide models as surrogates for the primary sequence dependence of peptide and protein deamidation rates and the discovery by difference of secondary, tertiary and quaternary structure effects. Deamidation of the pentapeptide models, compared with that of longer peptides of more intricate structure, is discussed, and the application of this technique to deamidation measurement of intact proteins is demonstrated.

Amides↗

PubMed2000

A structural model of transcription elongation.

The path of the nucleic acids through a transcription elongation complex was tracked by mapping cross-links between bacterial RNA polymerase (RNAP) and transcript RNA or template DNA onto the x-ray crystal structure. In the resulting model, the downstream duplex DNA is nestled in a trough formed by the beta' subunit and enclosed on top by the beta subunit. In the RNAP channel, the RNA/DNA hybrid extends from the enzyme active site, along a region of the beta subunit harboring rifampicin resistance mutations, to the beta' subunit "rudder." The single-stranded RNA is then extruded through another channel formed by the beta-subunit flap domain. The model provides insight into the functional properties of the transcription complex.

Binding Sites↗

PubMed2002

Structural model of the transmembrane Fo rotary sector of H+-transporting ATP synthase derived by solution NMR and intersubunit cross-linking in situ.

H(+)-transporting, F(1)F(o)-type ATP synthases utilize a transmembrane H(+) potential to drive ATP formation by a rotary catalytic mechanism. ATP is formed in alternating beta subunits of the extramembranous F(1) sector of the enzyme, synthesis being driven by rotation of the gamma subunit in the center of the F(1) molecule between the alternating catalytic sites. The H(+) electrochemical potential is thought to drive gamma subunit rotation by first coupling H(+) transport to rotation of an oligomeric rotor of c subunits within the transmembrane F(o) sector. The gamma subunit is forced to turn with the c-oligomeric rotor due to connections between subunit c and the gamma and epsilon subunits of F(1). In this essay we will review recent studies on the Escherichia coli F(o) sector. The monomeric structure of subunit c, determined by NMR, shows that subunit c folds in a helical hairpin with the proton carrying Asp(61) centered in the second transmembrane helix (TMH). A model for the structural organization of the c(10) oligomer in F(o) was deduced from extensive cross-linking studies and by molecular modeling. The model indicates that the H(+)-carrying carboxyl of subunit c is occluded between neighboring subunits of the c(10) oligomer and that two c subunits pack in a "front-to-back" manner to form the H(+) (cation) binding site. In order for protons to gain access to Asp(61) during the protonation/deprotonation cycle, we propose that the outer, Asp(61)-bearing TMH-2s of the c-ring and TMHs from subunits composing the inlet and outlet channels must turn relative to each other, and that the swiveling motion associated with Asp(61) protonation/deprotonation drives the rotation of the c-ring. The NMR structures of wild-type subunit c differs according to the protonation state of Asp(61). The idea that the conformational state of subunit c changes during the catalytic cycle is supported by the cross-linking evidence in situ, and two recent NMR structures of functional mutant proteins in which critical residues have been switched between TMH-1 and TMH-2. The structural information is considered in the context of the possible mechanism of rotary movement of the c(10) oligomer during coupled synthesis of ATP.

Adenosine Triphosphate↗

PubMed2001

Construction and analysis of base-paired regions of the 16S rRNA in the 30S ribosomal subunit determined by constraint satisfaction molecular modelling.

Structure models for each of the secondary structure regions from the Escherichia coli 16S rRNA (58 separate elements) were constructed using a constraint satisfaction modelling program to determine which helices deviated from classic A-form geometry. Constraints for each rRNA element included the comparative secondary structure, H-bonding conformations predicted from patterns of base-pair covariation, tertiary interactions predicted from covariation analysis, chemical probing data, rRNA-rRNA crosslinking information, and coordinates from solved structures. Models for each element were built using the MC-SYM modelling algorithm and subsequently were subjected to energy minimization to correct unfavorable geometry. Approximately two-thirds of the structures that result from the input data are very similar to A-form geometry. In the remaining instances, the presence of internal loops and bulges, some sequences (and sequence covariants) and accessory information require deviation from A-form geometry. The structures of regions containing more complex base-pairing arrangements including the central pseudoknot, the 530 region, and the pseudoknot involving base-pairing between G570-U571/A865-C866 and G861-C862/G867-C868 were predicted by this approach. These molecular models provide insight into the connection between patterns of H-bonding, the presence of unpaired nucleotides, and the overall geometry of each element.

Base Pairing↗

PubMed1999

Towards a structural model of an integrin.

Integrins are currently viewed as the principal family of extracellular matrix receptors. The interactions mediated by integrins are responsible for certain typical properties of adhesive cells, such as attachment and migration, but these molecules are also recognized to contribute to intracellular signalling processes, either by transducing signals themselves or by enabling and/or coordinating signalling via other receptor systems. As yet, the structural basis of integrin function is unknown, although detailed computer-based predictions have suggested working models for integrin tertiary structure. In this chapter, I will review this information and discuss recent studies examining the molecular basis of integrin regulation using stimulatory and inhibitory monoclonal antibodies (mAbs). Through the use of sensitive isolated integrin-binding assays, stimulatory mAbs have been found to function either by inducing shape changes in integrins or by selectively recognizing and stabilizing active and ligand-occupied conformations of integrins, while blocking mAbs were found to be allosteric inhibitors of ligand binding that report specific ligand engagement events. This information has improved our understanding of the composition of the integrin ligand-binding pocket and the structural basis of integrin activation.

Antibodies, Monoclonal↗