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PubMed1984

A structural model of human erythrocyte band 2.1: alignment of chemical and functional domains.

Protein 2.1 is a 210-kilodalton protein that connects erythrocyte spectrin to the NH2-terminal cytoplasmic domain of band 3 and thereby functions as the essential linkage between the membrane skeleton and the bilayer. We cleaved this protein into specific chemical domains by limited digestion with trypsin and alpha-chymotrypsin at 0 degrees C. Intermediate-sized peptides were separated by two-dimensional isoelectric focusing/NaDodSO4/polyacrylamide gel electrophoresis and characterized by high resolution peptide mapping. We have established a provisional structural model of protein 2.1 by comparing the peptide maps of these chemical domains to maps obtained from larger overlapping chymotryptic fragments as well as fragments obtained from 2-nitro-5-thiocyanobenzoic acid cleavage. In addition to providing a provisional structural map of protein 2.1, we have identified two functional domains of protein 2.1, an 83-kilodalton tryptic peptide (T-83) which binds band 3 and a 65-kilodalton tryptic peptide (T-65) which binds spectrin. We have therefore localized the functional domains along our linear map of protein 2.1.

Anion Exchange Protein 1, Erythrocyte↗

PubMed2004

Novel scoring function for modeling structures of oligomers of transmembrane alpha-helices.

Specific non-covalent interactions between transmembrane (TM) alpha-helices are important in a variety of biological processes. Experimental and computational studies have shown that van der Waals interactions play an important role in the tight packing between TM alpha-helices, although polar interactions can also be important in some instances. Based on the assumption that van der Waals interaction alone is sufficient for a meso-scale (residue-scale) description of the interaction between TM alpha-helices, we have designed a novel residue-scale scoring function for modeling structures of oligomers of TM alpha-helices. We first calculated atomistic van der Waals interaction energies between two amino acids, X and Y, of a pair of parallel alpha-helices, glycine-X-glycine and glycine-Y-glycine and compiled them according to three variables, the distance between the two C(alpha) atoms and the rotational angles of X and Y about their helical axes. Upon averaging over the rotational angles, we obtained one-dimensional interaction energy profiles that are functions of the distance between C(alpha) atoms only. Each of the interaction energy profiles was fitted with a generic fitting function of the distance between C(alpha) atoms, yielding analytical scoring functions for all possible amino acid pairs. For glycophorin A, neu/erbB-2, and phospholamban, lowest-energy conformations obtained through exhaustive scanning of the entire conformational space using the scoring functions were compatible with available experimental data.

Amino Acid Sequence↗

PubMed2005

Synthesis and properties of new glucocationic surfactants: model structures for marking cationic surfactants with carbohydrates.

[reaction: see text] In this work, we report the synthesis of a new series of glucocationic surfactants, a class of surfactants we introduced very recently. The preparation of the surfactants is based on the synthesis of the 2-bromoethyl-2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside, whose preparation was studied in order to improve yields and stereoselectivity of this key intermediate. These glucocationic amphiphiles were prepared and studied as a model of cationic surfactants marked with a carbohydrate moiety. The use of carbohydrates as markers on cationic lipids was recently introduced to induce recognition by specific receptors, present on the surface of cell membranes. The chemicophysical characterization of these model structures can give more insight on the aggregation behavior. Conductivity and surface tension measurements were performed in order to characterize the compounds from the amphiphilic point of view. The results showed a different effect of the glucosidic moiety on the cmc value with respect to the glucopyridinium cationic surfactants. The surfactants also showed the tendency to form premicellar aggregates in solution when the hydrophobicity is raised.

Carbohydrate Conformation↗

PubMed1996

Mutational analysis and secondary structure model of the RNP1-like sequence motif of transcription termination factor Rho.

The function of transcription termination factor Rho from Escherichia coli is dependent upon its ability to bind to specific sites on nascent RNA molecules. The roles of 19 individual amino acid residues (Ile49 to Ser67) in and near a phylogenetically conserved sequence segment of Rho that is similar to the RNP1 motif found in many RNA-binding proteins were examined by testing the phenotypic consequences of mutational changes that were introduced into rho by a random-sequence cassette mutagenesis procedure. The tests of each mutant included the ability of the cells to survive at 42 degrees C in the absence of wild-type rho, the efficiency of termination at a Rho-dependent terminator (lambdatR1) in vivo, the relative level of expression of the mutant protein, and the ability of some of the mutant proteins to bind RNA. The results revealed that residues in the RNP1-like sequence of DGFGFLR (residues 60 to 66) were more important than residues 49 to 59 for termination function and RNA binding, and identified three residues that were particularly sensitive to mutation: Asp60, Phe62 and Arg66. The properties of the mutants are consistent with a secondary structure model, derived from phylogenetic analysis, that has the RNP1-like sequence on one of the three beta-strands of an antiparallel beta-sheet with Asp60 and Gly61 in a turn and the side-chains of Phe62, Phe64 and Arg66 accessible on the same face of the beta-structure for interaction with RNA.

Amino Acid Sequence↗

PubMed1998

N-linked glycosylation of the thyroid Na+/I- symporter (NIS). Implications for its secondary structure model.

The Na+/I- symporter (NIS), a 618-amino acid membrane glycoprotein that catalyzes the active accumulation of I- into thyroid cells, was identified and characterized at the molecular level in our laboratory (Dai, G., Levy, O., and Carrasco, N. (1996) Nature 379, 458-460). Because mature NIS is highly glycosylated, it migrates in SDS-polyacrylamide gel electrophoresis as a broad polypeptide of higher molecular mass (approximately 90-110 kDa) than nonglycosylated NIS (approximately 50 kDa). Using site-directed mutagenesis, we substituted both separately and simultaneously the asparagine residues in all three putative N-linked glycosylation consensus sequences of NIS with glutamine and assessed the effects of the mutations on function and stability of NIS in COS cells. All mutants were active and displayed 50-90% of wild-type NIS activity, including the completely nonglycosylated triple mutant. This demonstrates that to a considerable extent, function and stability of NIS are preserved in the partial or even total absence of N-linked glycosylation. We also found that Asn225 is glycosylated, thus proving that the hydrophilic loop that contains this amino acid residue faces the extracellular milieu rather than the cytosol as previously suggested. We demonstrated that the NH2 terminus faces extracellularly as well. A new secondary structure model consistent with these findings is proposed.

Amino Acid Sequence↗

PubMed2005

Structural modeling and environmental regulation of arginine decarboxylase in Synechocystis sp. PCC 6803.

Arginine decarboxylase (ADC) is the first enzyme in the alternative route to putrescine in the polyamine biosynthesis pathway in bacteria and plants. In this study, we have focused on the effects of various types of short-term stresses on the transcript amount and specific activity of Synechocystis sp. PCC 6803 ADC. Our results reveal that the steady-state transcript accumulation and enzyme activity are not connected in a simple manner, since only photoheterotrophy and synergistic salt and high-light stress affected both parameters similarly. Changes in the steady-state ADC mRNA accumulation under the other short-term stress conditions studied had only a small impact on enzyme activity, suggesting post-translational regulation. Based on structural modeling, Synechocystis ADCs have a putative extra domain, which might be involved in the post-translational regulation of ADC activity in Synechocystis. In addition, two symmetric inter-subunit disulfide bonds seem to stabilize the dimeric structure of ADCs. There are two genes coding for ADC and agmatinase, another polyamine pathway enzyme, in Synechocystis genome, while the genes coding for ornithine decarboxylase and for some other enzymes in the polyamine pathway were not identified with homology searches.

Amino Acid Sequence↗

PubMed2005

Optimal strategy for structured model of fishing problem.

In this work we study a structured fishing model, basically displaying the two stages of the ages of a fish population, which are in our case juvenile, and adults. We associate to this model the maximization of the total discounted net revenues derived by the exploitation of the stock. The exploitation strategy of the optimal control problem is then developed and presented.

Animals↗

PubMed1995

A structural model for the mechanisms of elicitor release from fungal cell walls by plant beta-1,3-endoglucanase.

The release of elicitor-active carbohydrates from fungal cell walls by beta-1,3-endoglucanase contained in host tissues has been implicated as one of the earliest processes in the interaction between soybean (Glycine max) and the fungal pathogen Phytophthora megasperma f. sp. glycinea leading to host defense responses such as phytoalexin production. The present study was conducted to evaluate the primary structure of the glucanase-released elicitor (RE). Gel-filtration chromatography of carbohydrates released from mycelial walls by purified soybean beta-1,3-endoglucanase resolved them into the four fractions (elicitor-active RE-I, -II, and -III and elicitor-inactive RE-IV). Sugar composition analysis indicated that all of the fractions were composed almost entirely of glucose. 1H- and 13C-nuclear magnetic resonance analysis indicated the presence of both beta-1,3- and beta-1,6-linkages for the elicitor-active RE-I, -II, and -III fractions and only beta-1,3 linkage for the elicitor-inactive RE-IV fraction. Methylation analysis and degradation studies employing beta-1,3-endo- and beta-1,3-exoglucanase further suggested that the basic structure of elicitor-active RE consists of beta-1,6-linked glucan backbone chains of various lengths with frequent side branches composed of beta-1,3-linked one or two glucose moieties. From these structural analyses of RE, a structural model of how RE is originally present in fungal cell walls and released by host beta-1,3-endoglucanase is also proposed.

Carbohydrate Sequence↗

PubMed1999

Periodic intensity distribution (PID) of mica polytypes: symbolism, structural model orientation and axial settings.

Following a preliminary revisitation of the nomenclatures in use for mica polytypes, the properties of the periodic intensity distribution (PID) function, which represents the Fourier transform of the stacking sequence, are analysed. On the basis of the relative rotations of neighbouring layers, mica polytypes are classified into three types; for each type, the PID exists in different subspaces of the reciprocal space. A revised procedure to compute the PID, in which further restrictions on the structural model orientation are introduced, is presented. A unifying terminology based upon the most common symbols used to describe mica polytypes (RTW, Z and TS) is derived; these symbols represent the geometrical basis for the computation of the PID. Results are presented for up to four layer polytypes and are compared with the reflection conditions derived by means of Zvyagin's functions. Both the PID values and the reflection conditions are expressed in suitable axial settings and compared with previous partial reports, revealing some errors in previous analyses. A computer program to compute PID from the stacking symbols is available.

Journal Article↗

PubMed2002

A 3D structure model of integrin alpha 4 beta 1 complex: I. Construction of a homology model of beta 1 and ligand binding analysis.

It is well established that integrin alpha 4 beta 1 binds to the vascular cell adhesion molecule (VCAM) and fibronectin and plays an important role in signal transduction. Blocking the binding of VCAM to alpha 4 beta 1 is thought to be a way of controlling a number of disease processes. To better understand how various inhibitors might block the interaction of VCAM and fibronectin with alpha 4 beta 1, we began constructing a structure model for the integrin alpha 4 beta 1 complex. As the first step, we have built a homology model of the beta 1 subunit based on the I domain of the integrin CD11B subunit. The model, including a bound Mg(2+) ion, was optimized through a specially designed relaxation scheme involving restrained minimization and dynamics steps. The native ligand VCAM and two highly active small molecules (TBC772 and TBC3486) shown to inhibit binding of CS-1 and VCAM to alpha 4 beta 1 were docked into the active site of the refined model. Results from the binding analysis fit well with a pharmacophore model that was independently derived from active analog studies. A critical examination of residues in the binding site and analysis of docked ligands that are both potent and selective led to the proposal of a mechanism for beta 1/beta 7 ligand binding selectivity.

Amino Acid Sequence↗

PubMed2004

Estimation of maximal reliability: a note on a covariance structure modelling approach.

A one-step covariance structure analysis procedure for estimation of maximal reliability of linear composites with congeneric measures is outlined. The approach is readily employed within a single modelling session using popular covariance structure analysis software, and permits simultaneous estimation of the optimal measure weights with standard errors. The method is illustrated by a numerical example.

Humans↗

PubMed2006

Voltage sensor conformations in the open and closed states in ROSETTA structural models of K(+) channels.

Voltage-gated ion channels control generation and propagation of action potentials in excitable cells. Significant progress has been made in understanding structure and function of the voltage-gated ion channels, highlighted by the high-resolution open-state structure of the voltage-gated potassium channel, K(v)1.2. However, because the structure of the closed state is unknown, the gating mechanism remains controversial. We adapted the rosetta membrane method to model the structures of the K(v)1.2 and KvAP channels using homology, de novo, and domain assembly methods and selected the most plausible models using a limited number of experimental constraints. Our model of K(v)1.2 in the open state is very similar in overall topology to the x-ray structure of this channel. Modeling of KvAP in the open state suggests that orientation of the voltage-sensing domain relative to the pore-forming domain is considerably different from the orientation in the K(v)1.2 open state and that the magnitude of the vertical movement of S4 is significantly greater. Structural modeling of closed state of K(v)1.2 suggests gating movement that can be viewed as a sum of two previously suggested mechanisms: translation (2-4 A) plus rotation ( approximately 180 degrees ) of the S4 segment as proposed in the original "sliding helix" or "helical screw" models coupled with a rolling motion of the S1-S3 segments around S4, similar to recent "transporter" models of gating. We propose a unified mechanism of voltage-dependent gating for K(v)1.2 and KvAP in which this major conformational change moves the gating charge across the electric field in an analogous way for both channels.

Cell Membrane↗

PubMed2004

Model structures of the N-methyl-D-aspartate receptor subunit NR1 explain the molecular recognition of agonist and antagonist ligands.

Molecular models of the ligand-binding domain of N-methyl-d-aspartate subunit R1 (NR1) were made using the published crystal structures of rat glutamate receptor B (GluRB), the bacterial glutamate receptor (GluR0), and the glutamine-binding protein (QBP) of Escherichia coli. Separate models of NR1 were built to represent the ligand-binding conformation for agonist (glycine, d- and l-isomers of serine and alanine, and the partial agonist ligand d-cycloserine) and antagonist (5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (DCKA) and E-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1-H-indole-2-carboxylic acid (MDL 105,519)) ligands. Side-chain conformations of residues within the NR1 ligand-binding site were selected that optimized the hydrophobic packing and hydrogen bonding among residues, while taking into account published data comparing receptor mutants with wild-type NR1. Ligands docked to the model structures provide a rational explanation for the observed differences in binding affinity and receptor activation among agonist and antagonist ligands. NR1 prefers smaller ligands (glycine, serine, and alanine) in comparison with GluRB and GluR0 that bind l-glutamate: the bulky side chain of W731 in NR1 dramatically reduces the size of the ligand-binding site, functioning to selectively restrict recognition to glycine and the d-isomers of serine and alanine. Nevertheless, many of the interactions seen for ligands bound to GluRB, GluR0, and periplasmic-binding proteins are present for the ligands docked to the model structures of NR1.

Alanine↗

PubMed2002

Estimating the causal effect of zidovudine on CD4 count with a marginal structural model for repeated measures.

Even in the absence of unmeasured confounding factors or model misspecification, standard methods for estimating the causal effect of a time-varying treatment on the mean of a repeated measures outcome (for example, GEE regression) may be biased when there are time-dependent variables that are simultaneously confounders of the effect of interest and are predicted by previous treatment. In contrast, the recently developed marginal structural models (MSMs) can provide consistent estimates of causal effects when unmeasured confounding and model misspecification are absent. We describe an MSM for repeated measures that parameterizes the marginal means of counterfactual outcomes corresponding to prespecified treatment regimes. The parameters of MSMs are estimated using a new class of estimators - inverse-probability of treatment weighted estimators. We used an MSM to estimate the effect of zidovudine therapy on mean CD4 count among HIV-infected men in the Multicenter AIDS Cohort Study. We estimated a potential expected increase of 5.4 (95 per cent confidence interval -1.8,12.7) CD4 lymphocytes/l per additional study visit while on zidovudine therapy. We also explain the theory and implementation of MSMs for repeated measures data and draw upon a simple example to illustrate the basic ideas.

Anti-HIV Agents↗

PubMed2002

Structural model of the muscle spindle.

A model of the muscle spindle was developed based on its anatomical structure. The model contains three intrafusal fibers (bag1, bag2, and chain), two efferents (dynamic gamma efferent to the bag1 fiber and static gamma efferent to bag2 and chain fibers), and two afferents [primary (Ia) and secondary (II)]. As in the real muscle spindle, the spindle model, under the modulation of gamma efferents, responds to the extrafusal muscle fiber length. Both outputs (Ia and II afferents) of the model were compared extensively with published data, under both sinusoidal stretch (with different stretch amplitudes and frequencies) and ramp and hold stretch (with different stretch amplitudes and velocities) in three different fusimotor activation conditions (dynamic gamma stimulation, static gamma stimulation, and without gamma stimulation). Model Ia afferent responses fit the published data well with active gamma input, but less well in the passive state. Model II afferent responses also fit the published data, although less quantitative data were available for comparison. The model correctly predicted the fractional power dependence of the primary and secondary ending responses on stretch velocity. The current model provides a powerful tool for simulation studies of neuromusculoskeletal systems, and demonstrates the feasibility of using a structural approach to model complex neurophysiological systems.

Algorithms↗

PubMed2001

Solid-state NMR data support a helix-loop-helix structural model for the N-terminal half of HIV-1 Rev in fibrillar form.

Rev is a 116 residue basic protein encoded by the genome of human immunodeficiency virus type 1 (HIV-1) that binds to multiple sites in the Rev response element (RRE) of viral mRNA transcripts in nuclei of host cells, leading to transport of incompletely spliced and unspliced viral mRNA to the cytoplasm of host cells in the latter phases of the HIV-1 life cycle. Rev is absolutely required for viral replication. Because Rev aggregates and fibrillizes in solution at concentrations required for crystal growth or liquid state NMR measurements, high-resolution structural characterization of full-length Rev has not been possible. Previously, circular dichroism studies have shown that approximately 50 % of the Rev sequence adopts helical secondary structure, predicted to correspond to a helix-loop-helix structural motif in the N-terminal half of the protein. We describe the application of solid-state NMR techniques to Rev fibrils as a means of obtaining site-specific, atomic-level structural constraints without requiring a high degree of solubility or crystallinity. Solid-state NMR measurements, using the double-quantum chemical shift anisotropy and constant-time double-quantum-filtered dipolar recoupling techniques, provide constraints on the phi and psi backbone dihedral angles at sites in which consecutive backbone carbonyl groups are labeled with (13)C. Quantitative analysis of the solid-state NMR data, by comparison with numerical simulations, indicates helical phi and psi angles at residues Leu13 and Val16 in the predicted helix 1 segment, and at residues Arg39, Arg 42, Arg43, and Arg44 in the predicted helix 2 segment. These data represent the first site-specific structural constraints from NMR spectroscopy on full-length Rev, and support the helix-loop-helix structural model for its N-terminal half.

Amino Acid Sequence↗

PubMed2006

Examination of spinel and nonspinel structural models for gamma-Al2O3 by DFT and rietveld refinement simulations.

Despite the widespread use of gamma-Al2O3, there is still considerable disagreement over the nature of its structure due to both its poor crystallinity and differing preparation techniques during experimentation. Using density-functional theory (DFT) calculations and Rietveld simulations and refinement, the structure of three spinel-related models and a recently proposed nonspinel model were studied in reference to synchrotron X-ray powder diffraction (SXPD) patterns. The spinel-based structural models represent the structural features of gamma-Al2O3 better than the nonspinel model. The major failure of the nonspinel model is that the model cannot reproduce the SXPD reflection originating from tetrahedral aluminum. The Rietveld-refined spinel model can accurately reproduce the lattice parameters and other structural features of gamma-Al2O3, and it can generate a consistent diffraction peak at 2theta which lies between the splitting peaks of the experimental pattern that are originated from the disordered tetrahedral aluminum cations.

Journal Article↗

PubMed1996

Trimeric assembly and three-dimensional structure model of the FACIT collagen COL1-NC1 junction from CD and NMR analysis.

The 3D structure of the COL1-NC1 junction of FACIT type XIV collagen was investigated using GYCDPSSCAG and (GPP*)3GYCDPSSCAG synthetic peptides, circular dichroism, and NMR. At -20 degrees C and under air oxidation catalyzed by Cu2+, the peptide (GPP*)3GYCDPSSCAG is able to self-associated with high yield into a stable triple disulfide bonded trimer. The presence of a triple helical conformation was confirmed by circular dichroism. The analysis of the trimer by 2D NMR provided a set of distance constraints for the noncollagenous part. Molecular models for the 3D structure of COL1-NC1 junction were calculated, using the NMR distance constraints in combination with the 3D structural data recently established by X-ray crystallography [Bella, J., Eaton, M., Brodsky, B., & Berman, H. M. (1994) Science 266, 75-81] for a collagenous triple helix. From the eight theoretically possible arrangements for the three interchain disulfide bonds, only two close disulfide conformers are compatible with the experimental data. The main feature of the trimer structure is the asymmetry of the molecule due to the disulfide bond pattern that induces a particular folding of one chain. This chain forms a turn-like structure locked by two disulfide bonds with the two other chains. The turn-like folding is close to that observed for the cyclized oxidized monomeric peptide. This is the first report of the 3D structure model for a junction between a collagenous triple helical domain and a noncollagenous domain.

Amino Acid Sequence↗