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PubMed1986

Polydepsipeptides. 13. Synthesis and 1H-n.m.r. analysis of collagen model structures.

The synthesis of three collagen model analogs is described: Ac-Ala-Gly-Pro-Ala-Gly-Pro-NHMe, Ac-Ala-Gly-Pro-Ala-Glc-Pro-NHMe, and Ac-Ala-Glc-Pro-Ala-Gly-Pro-NHMe, where Glc stands for glycolic acid. The 1H-n.m.r. properties of these compounds in dimethylsulfoxide-d6 and trifluoroethanol are described. While in DMSO-d6 the compounds are random, in TFE the glycine amide protons seem to be less solvent exposed than the other amide protons. Little difference was found in the behavior of the three compounds.

Amino Acid Sequence↗
PubMed1996

Model structure of decorin and implications for collagen fibrillogenesis.

The three-dimensional structure of human decorin, a secreted proteoglycan involved in the regulation of collagen fibrillogenesis and cellular growth, has been modeled based on the crystal structure of the porcine ribonuclease inhibitor. Both proteins contain leucine-rich repeats and share 18% identical residues. This model structure of decorin has an arch shape with the single glycosaminoglycan chain and the three N-linked oligosaccharides located on the same side of the molecule. Decorin was modeled as binding to a polar sequence of collagen type I found in the d band. The inner concave surface is the appropriate size and shape to accommodate only one collagen triple helix of approximately 3 nm in length. The binding of one collagen triple helix to decorin is proposed to play a major role in the formation of the staggered arrangement of collagen molecules within the microfibrils by preventing lateral fusion of collagen molecules.

Amino Acid Sequence↗
PubMed1999

Molecular dynamics model structures for the molten globule state of alpha-lactalbumin: aromatic residue clusters I and II.

To model the molten globule structure of alpha-lactalbumin, molecular dynamics (MD) simulations were carried out for the protein in explicit water at high temperature. In these simulations, long-range Coulomb interactions were evaluated explicitly with an original method (particle-particle and particle-cell: PPPC) to avoid artifacts caused by the cut-off. The MD simulations were started from two initial conditions to verify that similar results would be obtained. From the last 150 ps trajectories of the two MD simulations, two partially unfolded average structures were obtained. These structures had the following common structural features which are characteristic of the molten globule state. The radii of gyration for these conformations were 7.4 and 9.6% larger than that of the native state. These values were almost the same as the experimental value (9.6%) observed recently by small-angle X-ray scattering (Kataoka,M., Kuwajima,K., Tokunaga,F. and Goto,Y., 1997, Protein Sci., 6, 422-430). Furthermore, aromatic residues of clusters I and II in these structures were far apart from each other except for Try103-Trp104. This result is in good agreement with NMR experimental results for the acid-denatured molten globule state (Alexandrescu et al., 1992, 1993); that is, NOE signals between the aromatic residues were not observed, except for that of Try103-Trp104 in the molten globule state. Other structural features of these models for the molten globule state are discussed with reference to native state structures.

Animals↗
PubMed1994

Molecular dynamics studies on peroxidases: a structural model for horseradish peroxidase and a substrate adduct.

Molecular dynamics (MD) calculations are performed on cytochrome c peroxidase (CcP) and on horseradish peroxidase, isoenzyme C (HRP), and its substrate adduct with p-cresol. For CcP, a refinement in solution of the X-ray structure is obtained which indicates that in solution the protein structure is very similar to that in the crystal. For HRP, the X-ray structure is not available. We have generated a model of this protein based on the recently reported structure of the similar lignin peroxidase (LiP) protein. This model involves the entire system as all the amino acid residues match the sequence. This HRP model was refined through energy minimization and MD calculations. A refined structural model for HRP, for the first time involving the entire protein, is therefore now available. The tertiary structure of HRP is close to that of LiP, and also the active site in the two proteins has significantly similar structures. The well-ordered water molecules and the extensive H-bond network present in the X-ray structure of CcP is maintained in the dynamics without any constraints, indicating that the active site residues produce a field strong enough to make all these interactions quite stable. Interestingly, also in HRP a network of ordered water molecules and H-bonds is present, again without constraints. This is consistent with the similarities of the active sites in the two proteins. Finally, we have calculated the MD structure of the adduct of HRP and a substrate molecule, p-cresol. This structural model is compared with the NMR data, which are in fairly good agreement. The binding site and the protein-substrate interactions are discussed.

Binding Sites↗
PubMed2026

Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome.

With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Establishing pathogenicity requires a multidisciplinary approach that integrates genetic, structural, functional, and clinical data. Here, we used such a strategy to investigate a previously unreported hemizygous missense variant - alanine (A) to threonine (T) at residue 518 - in Toll-like receptor 8 (TLR8), identified in 2 male siblings with recurrent infections and systemic inflammation, characterized by a proinflammatory immune signature and B cell dysregulation. Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect. Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation. Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution. Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in 2 siblings.

Humans↗
PubMedDate not supplied

An energetically structured model of mammalian cell metabolism. 1. Model development and application to steady-state hybridoma cell growth in continuous culture.

Incomplete understanding of mammalian cell culture kinetics hinders the ability of the biochemical engineer or biologist to design and control mammalian cell culture systems and to develop operating strategies. To address this problem, a mechanistic, structured mathematical model has been developed to simulate mammalian cell culture kinetics under a variety of bioreactor operating conditions. An important feature of in vitro mammalian cell metabolism in conventional cell culture media is the partial substitutability of the substrates glucose and glutamine for provision of energy in the cell. The utilization of glucose and glutamine by cells can therefore vary substantially, and these changes can profoundly affect the culture behavior. The model developed here specifically addresses the dynamics of substrate consumption and energy metabolism in mammalian cell culture. This energetically structured (ES) model is also distinguished by the consideration of changes in the specific cell mass with specific growth rate and the consideration of essential amino acids as potentially growth rate limiting. The model is applied here to simulate literature data on the growth and metabolism of a murine hybridoma in continuous culture.

Animals↗
PubMed1977

[Small-angle X-ray-scattering investigation and structural-model study of the fatty-acid synthetase from pig liver (author's transl)].

The structure of the fatty acid synthetase from pig liver was studied on models based upon structural and functional properties selected from pertinent results available from numerous investigations carried out with fatty acid synthetases from this and other sources. When comparing small-angle X-ray-scattering curves calculated with these models and curves obtained from small-angle X-ray-scattering experiments carried out with the pig-liver enzyme, we tried to select a model which would lead to an acceptable correlation between the calculated and the experimental curves and at the same time fulfil the known structural and functional requirements. The comparison of the curves was started with a model of low complexity. The observed discrepancy, together with arguments from the structural and the functional properties, helped decide which is the next most reasonable model to be considered. This procedure was repeated for five models of increasing complexity. In the model which led to the best fit the multienzyme complex is composed of two halves in an assymetric conformation including hollow spaces. This highly anisotropic model would imply that the two halves change their conformation each time a synthetic cycle is completed and that the growing fatty acid is handed over from one half to the other.

Animals↗
PubMed1990

Application of structural model of glucose-insulin relations to assess beta-cell function and insulin sensitivity.

A structural mathematical model of glucose-insulin relationships based on known quantitative responses of the major organs involved with glucose metabolism has been computed. Different degrees of beta-cell function and insulin sensitivity can be included, and the effect of their interaction assessed (i) in a steady state, basal homeostasis after an overnight fast and (ii) in response to a glucose infusion. By comparing a patient's basal plasma glucose and insulin (or C-peptide) concentrations with the predictions of a basal homeostatic model, the degree of impairment of beta-cell function and insulin sensitivity can be assessed. Similarly, the plasma glucose and insulin (or C-peptide) concentrations after a continuous glucose infusion can also be compared with predictions from the model to estimate beta-cell function and insulin sensitivity. These assessments of pathophysiology can be applied to data from individual patients or to patient populations.

Blood Glucose↗
PubMed1996

ABGEN: a knowledge-based automated approach for antibody structure modeling.

Immunoglobulin (Ig) amino acid sequences are highly conserved and often have sequence homology ranging from 70 to 95%. Antigen binding fragments (Fab), variable region fragments (Fv), and single chain Fv (scFv) of more than 50 myeloma proteins and monoclonal antibodies (mAb) have been crystallized and display a high degree of structural similarity. Based on this observation, several homology modeling approaches have been developed for the prediction of Fab and Fv structures prior to their experimental determination. We have extracted features from existing Ig sequences, 44 known Fab and Fv structures to create an automated AntiBody structure GENeration (ABGEN) algorithm for obtaining structural models of antibody fragments. ABGEN utilizes a homology based scaffolding technique, and includes the use of invariant and strictly conserved residues, structural motifs of known Fab, canonical features of hypervariable loops, torsional constraints for residue replacements and key inter-residue interactions. The validity of the ABGEN algorithm has been tested using a five-fold cross validation with the existing Fab structures. Molecular mechanics and dynamics methods have been implemented with ABGEN models to accurately predict two Fab structures of anti-sweetener antibodies prior to crystallographic determinations.

Algorithms↗
PubMed1991

Manganese superoxide dismutase from Thermus thermophilus. A structural model refined at 1.8 A resolution.

The structure of Mn(III) superoxide dismutase (Mn(III)SOD) from Thermus thermophilus, a tetramer of chains 203 residues in length, has been refined by restrained least-squares methods. The R-factor [formula: see text] for the 54,056 unique reflections measured between 10.0 and 1.8 A (96% of all possible reflections) is 0.176 for a model comprising the protein dimer and 180 bound solvents, the asymmetric unit of the P4(1)2(1)2 cell. The monomer chain forms two domains as determined by distance plots: the N-terminal domain is dominated by two long antiparallel helices (residues 21 to 45 and 69 to 89) and the C-terminal domain (residues 100 to 203) is an alpha + beta structure including a three-stranded sheet. Features that may be important for the folding and function of this MnSOD include: (1) a cis-proline in a turn preceding the first long helix; (2) a residue inserted at position 30 that distorts the helix near the first Mn ligand; and (3) the locations of glycine and proline residues in the domain connector (residues 92 to 99) and in the vicinity of the short cross connection (residues 150 to 159) that links two strands of the beta-sheet. Domain-domain contacts include salt bridges between arginine residues and acidic side chains, an extensive hydrophobic interface, and at least ten hydrogen-bonded interactions. The tetramer possesses 222 symmetry but is held together by only two types of interfaces. The dimer interface at the non-crystallographic dyad is extensive (1000 A2 buried surface/monomer) and incorporates 17 trapped or structural solvents. The dimer interface at the crystallographic dyad buries fewer residues (750 A2/monomer) and resembles a snap fastener in which a type I turn thrusts into a hydrophobic basket formed by a ring of helices in the opposing chain. Each of the metal sites is fully occupied, with the Mn(III) five-co-ordinate in trigonal bipyramidal geometry. One of the axial ligands is solvent; the four protein ligands are His28, His83, Asp166 and His170. Surrounding the metal-ligand cluster is a shell of predominantly hydrophobic residues from both chains of the asymmetric unit (Phe86A, Trp87A, Trp132A, Trp168A, Tyr183A, Tyr172B, Tyr173B), and both chains collaborate in the formation of a solvent-lined channel that terminates at Tyr36 and His32 near the metal ion and is presumed to be the path by which substrate or other inner-sphere ligands reach the metal.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1995

Model structure of the Omp alpha rod, a parallel four-stranded coiled coil from the hyperthermophilic eubacterium Thermotoga maritima.

Omp alpha is an outer-membrane protein that spans the periplasmic space of the hyperthermophilic eubacterium Thermotoga maritima. The molecule contains a globular head with an apparent diameter of 8 nm and a rod-shaped tail of 40 nm length. The sequence of the globular domain is homologous to a conserved region of cell wall-bound proteins and probably attaches Omp alpha to the peptidoglycan. The sequence of the rod domain resembles that of coiled coil proteins and ends in a transmembrane segment that anchors Omp alpha to the outer membrane. We have analysed Omp alpha by scanning transmission electron microscopy (STEM) and by statistical sequence analysis methods. The Omp alpha rod is a tetramer with an unusual periodicity of hydrophobic residues close to 3.6 that differs from the 3.5 periodicity of canonical coiled coils. This is due to periodic omissions of three residues in the heptad repeat pattern ("stutters") whose effect is to locally distort the packing of hydrophobic layers in the core of the coiled coil. Residues in position alpha are shifted to occupy a position halfway between positions alpha and d (x layers) and residues in positions d and e are shifted so that both participate in core packing interactions (da layers). Such distorted layers are frequently found in helical bundles and are characteristic of helices that do not undergo supercoiling. The only homo-oligomeric coiled coil of known structure which contains x and da layers is the three-stranded coiled coil of influenza haemagglutinin. Using geometric constraints derived from this structure, we have built a model for the Omp alpha rod in which the helices have a crossing angle of less than 15 degrees and maintain a residual degree of supercoiling with a pitch of approximately 40 nm. Our analysis of distorted layers in the hydrophobic core of coiled coils and helical bundles shows that stutters must not be viewed as discontinuities but rather as a departure from the canonical "knobs-into-holes" packing that allows helices to interact at a low angle without supercoiling. Although stutters have been considered to weaken helical interactions, their occurrence in a rigid, highly thermostable coiled coil indicates that this may not be generally true. Our analysis also indicates that skips and stutters are two different conventions for describing the same underlying structural feature.

Amino Acid Sequence↗
PubMed1994

Structural model for the reaction mechanism of glutamine synthetase, based on five crystal structures of enzyme-substrate complexes.

Glutamine synthetase brings nitrogen into metabolism by condensing ammonia and glutamate, with the aid of ATP, to yield glutamine, ADP, and inorganic phosphate. Here we present five crystal structures of GS complexed with each of two substrates, Glu and AMPPNP (an ATP analog), with a transition-state analogue, L-methionine-S-sulfoximine, and with each of two products, Gln and ADP. GS of the present study is from Salmonella typhimurium, has Mn2+ bound, and is fully unadenylylated. Protein-metal-substrate interactions and small but significant conformational changes induced by substrate binding are defined by Fourier maps. On the basis of these maps, we propose a tentative structure-based enzymatic mechanism of glutamine synthesis with these steps: (1) ATP binds first at the top of the funnel-shaped active site cavity, adjacent to the n2 Mn2+; Arg 359 moves toward the Glu binding site. (2) Glu binds adjacent to the n1 Mn2+ at the bottom of the active site near a flexible loop (residues 324-328). As proposed earlier by Meister and others, Glu attacks the gamma-phosphorus atom of ATP to produce gamma-glutamyl phosphate and ADP. (3) The presence of ADP (but not ATP) moves Arg 339 toward the Pi site, perhaps stabilizing the gamma-glutamyl phosphate, and moves Asp 50' of the adjacent subunit toward a putative ammonium ion site, enhancing binding of this third substrate. Deprotonation of the ammonium ion, perhaps by Asp 50', permits the resulting active species, ammonia, to attack the gamma-glutamyl phosphate, forming a tetrahedral intermediate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Imidodiphosphate↗
PubMed1986

A common structural model for central nervous system drugs and their receptors.

On the basis of the hypothesis that there is a common structural basis for central nervous system (CNS) drug action consisting primarily of an aromatic group and a nitrogen atom, a four-point model for a common pharmacophore is defined with use of five semirigid CNS-active drug molecules: morphine, strychnine, LSD, apomorphine, and mianserin. Two of the points of the model represent possible hydrophobic interactions between the aromatic group and the receptor, while the other two represent hydrogen bonding between the nitrogen atom and the receptor. The model is then extended by the inclusion of nine additional CNS-active drug molecules: phenobarbitone, clonidine, diazepam, bicuculline, diphenylhydantoin, amphetamine, imipramine, chlorpromazine, and procyclidine, each being chosen as a key representative of a different CNS-active drug class or neurotransmitter system. Consideration of all phenyl group and nitrogen atom combinations, as well as all feasible conformations, shows that all nine molecules closely fit the common model in low-energy conformations. It is proposed that the model may eventually be used to design CNS-active drugs by mapping the relative locations of secondary binding sites. It can also be used to predict whether a given structure is likely to show CNS activity: a search over 1000 entries in the Merck Index shows a high probability of CNS activity in compounds fitting the common structural model.

Amphetamine↗
PubMed1985

Structural model of the collagen-like region of C1q comprising the kink region and the fibre-like packing of the six triple helices.

A detailed three-dimensional model of the collagenous part of C1q was derived by model building and computer-aided energy refinement calculations. The proposed structure is based on the collagen-like (-Gly-Xaa-Yaa-) repeating sequence of 78 to 81 residues in the N-terminal regions of the constituent A, B and C chains, on the mode of disulphide linkage between the 18 chains of C1q, and on its electron microscopically derived gross structure. It is demonstrated that the interruptions of the repeating sequence about half-way along the length of the collagenous regions (Gly36-Ile37-Arg38-Thr39 in the A chain and Ala36-Ile37-Hy138 in the C chain) do not lead to a disruption of the triple helical conformation but rather to a bend of about 60 degrees in an otherwise continuous triple helix. These features are consistent with a flexibility comparable with that of regular triple helices and with the observed low proteolytic susceptibility of the kink region. The azimuthal orientation of the kink is defined approximately by ArgA38 being located in the cap of the knee. Because of this extra residue between two glycine residues, a bad contact that would arise between the methyl group of AlaC36 and the peptide carbonyl of IleA37 in a straight triple helix is relaxed. The model features also a cluster of hydrophobic contacts between large hydrophobic side-chains in the interaction edges between the six collagen triple helices aligned with their about 10 nm long N-terminal regions in the fibril-like endpiece of C1q. The azimuthal orientations of the triple helices were derived by energy calculations of side-chain interactions previously applied to fibre-forming collagens. Independently, the same orientations and interaction edges were derived from the azimuthal orientation of the kink and the electron microscopically observed orientations of the triple helical arms that emerge from the endpiece, and which carry the C-terminal globular binding domains. The structural model has a number of implications for the assembly of the first component of complement from C1q and the zymogen complex C1r2C1s2 and possible mechanisms of its activation.

Amino Acid Sequence↗
PubMed1999

Computationally derived structural models of the beta-amyloid found in Alzheimer's disease plaques and the interaction with possible aggregation inhibitors.

We report the modeling of and possible interactions within the solid beta-amyloid (ABeta) 1-43 fibril, the most fibrillogenic peptide known. All models proposed are consistent with the known experimental structural data, in terms of both secondary structure and packing motifs. The model containing antiparallel beta-sheets, and a beta-turn at G(25)S(26)N(27)K(28) has the lowest calculated packing energy. As such, it can be considered a reasonable model for solid beta-amyloid in Alzheimer's disease plaques. Interestingly, with the turn located at this position, the 1-43 structure is stabilized by a number of complementary intermolecular interactions between the beta-sheets. These well-defined interactions exist for the side-chain residues of 41, 42, and 43 with adjacent ABeta molecules. These interactions would not be conserved in the 1-40 peptide, and indeed, this enhanced interaction is proposed to give rise to the increased fibrillogenic nature of the ABeta 1-43 species over the 1-40 form. The models are used to explain the increased fibrillogenic nature of the Dutch family mutation of ABeta. These models are also employed to examine possible docking interactions of previously reported antiaggregation inhibitors, such as 4'-deoxy-4'-iododoxorubicin (IDOX) onto the theoretical growing surface. A docked structure of IDOX with the model of the solid fibril is described and a proposal for the mechanism of its antiaggregation properties is presented.

Alzheimer Disease↗
PubMed2000

Development of a tertiary-structure model of the C-terminal domain of DPP IV.

Based on the recently published structure of prolyl oligopeptidase (POP) a model of the C-terminal part of dipeptidyl peptidase IV (DPP IV) which contains the active site has been developed. The structure of the model of DPP IV shows considerable similarity to the structure of POP particularly in the active site. A hydrophobic pocket (Tyr666, Tyr670, Tyr 631, Val556) forms the S1-binding site for recognition of proline. Tyr547 may stabilise the oxyanion formed in the tetrahedral intermediates by a strong hydrogen bond. The positively charged N-terminus of ligands of DPP IV is recognised by forming a salt bridge with the acidic side chain Glu668. A second hydrophobic pocket (S2' to S5') may represent an important binding site for HIV-1 Tat-protein derivatives, chemokines and others.

Amino Acid Sequence↗
PubMed2000

A structural model for predicting mathematics achievement: its relation with anxiety and self-concept in mathematics.

This study proposed and tested a model of mathematics achievement and its relations to antecedent and subsequent factors using structural equations modeling. A sample of elementary school students in Al-Ain school district (n = 394) completed an Arabic version of the Self-description Questionnaire as well as a questionnaire measuring their perception of the importance of mathematics, anxiety about it, and the amount of effort they exerted in studying. Mathematics grades were obtained from the official school records. Importance and effort were positively related to achievement which in turn had a positive path coefficient to self-concept and a negative path to anxiety. The hypothesized model explained 40%, 64%, and 73% of the variance in achievement, self-concept, and anxiety, respectively. The results can be interpreted as indicating that achievement is an important outcome and antecedent construct within the proposed model.

Achievement↗
PubMed2000

The active site of drosomycin, a small insect antifungal protein, delineated by comparison with the modeled structure of Rs-AFP2, a plant antifungal protein.

Drosomycin is the first strictly antifungal protein isolated from an insect (Drosophila melanogaster). The solution structure of this 44-residue protein has been reported previously. It involves a three-stranded beta-sheet and an alpha-helix, the protein global fold being maintained by four disulfide bridges. Rs-AFP2 is a plant antifungal protein exhibiting 41% sequence similarity with drosomycin. Mutational analysis of Rs-AFP2 showed the importance of some residues in the antifungal activity of the protein against the fungus target. In order to determine the structural features responsible for antifungal activity in both drosomycin and Rs-AFP2, we modeled the three-dimensional structure of Rs-AFP2, and of other antifungal proteins, using the solution structure of drosomycin as a template. Structure analysis of drosomycin and Rs-AFP2, and comparisons with the other modeled antifungal structures, revealed that the two proteins shared a hydrophobic cluster located at the protein surface in which a lysine residue is embedded. Based on these close structural similarities and the experimental data available for Rs-AFP2 mutants, an antifungal active site of the insect protein is proposed.

Amino Acid Sequence↗