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  • 1
    ISSN: 1573-904X
    Keywords: IL-1R type I ; microcalorimetry ; protein formulation ; stability ; aggregation ; preservatives ; far-uv circular dichroism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To elucidate the solution conditions that confer stability of aqueous IL-1R using differential scanning calorimetry (DSC). Methods. Optimal pH conditions were determined by monitoring degradation products encountered during accelerated studies (at elevated temperatures) using SDS-PAGE. At the pH optimum, DSC screened for excipients that enhanced thermal stability by shifting the Tm to higher values. Using SEC the relationship between thermal unfolding and stability was investigated by considering if lower Tm's in the presence of preservatives correlated with degradation products at 37°C over time. The degree of aggregation relative to that of a control determined the level of stability achieved. Results. Circular dichroism (CD) measurements confirmed molecular modeling studies showing IL-1R to be about 39% β-sheet. Two major transitions characterized the DSC data with Tm's observed near 47°C and 66°C. Among 21 excipients screened, NaCl exhibited the greatest stabilizing influences based on shifting the low temperature transition to 53°C. The low temperature transition was later found to comprise two transitions, yielding a total of three melting transitions for IL-1R. High Tm's arising from the presence of preservatives correlated with the order of stability (i.e., 0.065% phenol 〉 0.1% m-Cresol 〉 0.9% benzyl alcohol). Conclusions. The three melting transitions are consistent in origin with the cooperative unfolding of three unique immunoglobulin-like domains of IL-1R. Optimal stability was achieved in 20 mM sodium citrate at pH 6 with sufficient NaCl to attain the tonicity of human serum. A correlation between the predicted ranking of stability and the extent of aggregation was demonstrated using DSC.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Soluble TNF-a is released by cleavage of the precursor at the Ala76-Val77 bond, and we have previously shown that TACE cleaves a 12-residue peptide spanning this site with the same specificity3'11. The enzyme was purified by following its activity with an assay for cleavage of this processing-site ...
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  • 3
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Company
    Nature biotechnology 11 (1993), S. 1579-1580 
    ISSN: 1546-1696
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: [Auszug] Imagine if every time you sequenced a gene you could get an approximation of the sequence's three-dimensional structure. A computer modeling system that related amino acid sequence to protein tertiary structure would provide researchers with quick insights. With large databases like those now being ...
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  • 4
    ISSN: 1600-0846
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Purpose: To explore texture features in two-dimensional images to differentiate seborrheic keratosis from melanoma.Methods: A systematic approach to consistent classification of skin tumors is described. Texture features, based on the second-order histogram, were used to identify the features or a combination of features that could consistently differentiate a malignant skin tumor (melanoma) from a benign one (seborrheic keratosis). Two hundred and seventy-one skin tumor images were separated into training and test sets for accuracy and consistency. Automatic induction was applied to generate classification rules. Data analysis and modeling tools were used to gain further insight into the feature space.Result and Conclusions: In all, 85–90% of seborrheic keratosis images were correctly differentiated from the malignant skin tumors. The features correlation_average, correlation_range, texture_energy_average and texture_energy_range were found to be the most important features in differentiating seborrheic keratosis from melanoma. Over-all, the seborrheic keratosis images were better identified by the texture features than the melanoma images.
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  • 5
    ISSN: 1573-4951
    Keywords: Brevotoxin ; Comparative modeling ; Enzyme-inhibitor complex ; Papain ; Cysteine-protease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary We have developed an approach to search for molecules that can be used as lead compounds in designing an inhibitor for a given proteolytic enzyme when the 3D structure of a homologous protein is known. This approach is based on taking the cast of the binding pocket of the protease and comparing its dimensions with that of the dimensions of small molecules. Herein the 3D structure of papain is used to model cathepsin L using the comparative modeling technique. The cast of the binding pocket is computed using the crystal structure of papain because the structures of papain and the model of cathepsin L are found to be similar at the binding site. The dimensions of the cast of the binding site of papain are used to screen for molecules from the Cambridge Structural Database (CSD) of small molecules. Twenty molecules out of the 80 000 small molecules in the CSD are found to have dimensions that are accommodated by the papain binding pocket. Visual comparison of the shapes of the cast and the 20 screened molecules resulted in identifying brevotoxin b, a toxin isolated from the ‘red tide’ dinoflagellate Ptycho brevis (previously classified as Gymonodium breve), as the structure that best fits the binding pocket of papain. We tested the proteolytic activity of papain and cathepsin L in the presence of brevotoxin b and found inhibition of papain and cathepsin L with Kis of 25 μM and 0.6 μM, respectively. We also compare our method with a more elaborate method in the literature, by presenting our results on the computer search for inhibitors of the HIV-1 protease.
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  • 6
    ISSN: 0887-3585
    Keywords: interleukin-4 ; circular dichroism spectroscopy ; site-directed mutagenesis ; protein structure modeling ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The structure of human interleukin 4 (IL-4) was predicted utilizing a series of experimental and theoretical techniques. Circular Dichroism (CD) spectroscopy indicated that IL-4 belonged to the all α-helix class of protein structures. Secondary structure prediction, site-directed mutagenesis, and CD spectroscopy suggested a predominantly α-helical structure, consistent with a four-helix bundle structural motif. A human/mouse IL-4 chimera was constructed to qualitatively evaluate alternative secondary structure predictions. The four predicted helices were assembled into tertiary structures using established algorithms. The mapping of three disulfide bridges in IL-4 provided additional constraints on possible tertiary structures. Using accessible surface contact area as a criterion, the most suitable structures were right handed all antiparallel four-helix bundles with two overhand loop connections. Successful loop closure and incorporation of the three disulfide constraints were possible while maintaining the expected shape, solvent accessibility, and steric interactions between loops and helices. Lastly, energy minimization was used to regularize the chain.
    Additional Material: 7 Ill.
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  • 7
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The scope of multistep modeling (MSM) is expanded by adding a least-squares minimization step in the procedure to fit backbone reconstruction consistent with a set of C-alpha coordinates. The analytical solution of Phi and Psi angles, that fits a C-alpha x-ray coordinate [1] is used for tyr-tRNA synthetase. Phi and Psi angles for the region where the above mentioned method fails, are obtained by minimizing the difference in C-alpha distances between the computed model and the crystal structure in a least-squares sense. We present a stepwise application of this part of MSM to the determination of the complete backbone geometry of the 321 N terminal residues of tyrosine tRNA synthetase to a root mean square deviation of 0.47 Å from the crystallographic C-alpha coordinates.
    Additional Material: 7 Ill.
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