Aktuelle Fachartikel zur Chemie von biologischen Makromolekuelen, sortiert nach Erscheinungsdatum.
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beruecksichtige naturwissenschaftliche Journale:
BMC Structural Biology - published by
BioMed Central -
... is an open access journal publishing original peer-reviewed research articles in investigations into the structure and function of biological macromolecules.
Biomacromolecules - published by
The American Chemical Society -
... explores the interactions of macromolecules with biological systems and their environments as well as biological approaches to the design of polymeric materials. Cutting-edge research at the interface of polymer science and biological sciences.
Aktuelle wissenschaftliche Fachartikel der
genannten Journale:
Thomas Abraham, Sarah R. Schooling, Terry J. Beveridge, and John Katsaras Web Release Date: Sat, 6 Sep 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800562r
Xiaofeng Sui, Jinying Yuan, Mi Zhou, Jun Zhang, Haijun Yang, Weizhong Yuan, Yen Wei, and Caiyuan Pan Web Release Date: Sat, 6 Sep 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800538d
Todd Lyle Kaneshiro, Eun-Kee Jeong, Glen Morrell, Dennis L. Parker, and Zheng-Rong Lu Web Release Date: Fri, 5 Sep 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800486c
Background:
The transcription factor NF-kappaB is a very interesting target molecule for the design on anti-tumor, anti-inflammatory and pro-apoptotic drugs. However, the application of the widely-used molecular docking computational method for the virtual screening of chemical libraries on NF-kappaB is not yet reported in literature. Docking studies on a dataset of 27 molecules from extracts of two different medicinal plants to NF-kappaB-p50 were performed with the purpose of developing a docking protocol fit for the target under study.
Results:
We enhanced the simple docking procedure by means of a sort of combined target- and ligand-based drug design approach. Advantages of this combination strategy, based on a similarity parameter for the identification of weak binding chemical entities, are illustrated in this work with the discovery of a new lead compound for NF-kappaB. Further biochemical analyses based on EMSA were performed and biological effects were tested on the compound exhibiting the best docking score. All experimental analysis were in fairly good agreement with molecular modeling findings.
Conclusion:
The results obtained sustain the concept that the docking performance is predictive of a biochemical activity. In this respect, this paper represents the first example of successfully individuation through molecular docking simulations of a promising lead compound for the inhibition of NF-kappaB-p50 biological activity and modulation of the expression of the NF-kB regulated IL8 gene.
Marian E. Gindy, Shengxiang Ji, Thomas R. Hoye, Athanassios Z. Panagiotopoulos, and Robert K. Prud’homme Web Release Date: Sat, 30 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm8002013
Tobias Ekblad, Gunnar Bergström, Thomas Ederth, Sheelagh L. Conlan, Robert Mutton, Anthony S. Clare, Su Wang, Yunli Liu, Qi Zhao, Fraddry D’Souza, Glen T. Donnelly, Peter R. Willemsen, Michala E. Pettitt, Maureen E. Callow, James A. Callow, and Bo Liedberg Web Release Date: Sat, 30 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800547m
Helder Marçal, Nico S. Wanandy, Vorapat Sanguanchaipaiwong, Catherine E. Woolnough, Antonio Lauto, Stephen M. Mahler, and L. John R. Foster Web Release Date: Fri, 29 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800418e
Jenny A. Lichter, M. Todd Thompson, Maricela Delgadillo, Takehiro Nishikawa, Michael F. Rubner, and Krystyn J. Van Vliet Web Release Date: Thu, 28 Aug 2008 00:00:00 EDT (Addition/Correction) DOI: 10.1021/bm8009335
C. N. N’soukpoé-Kossi, A. Ahmed Ouameur, T. Thomas, A. Shirahata, T. J. Thomas, and H. A. Tajmir-Riahi Web Release Date: Tue, 26 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800412r
D. Magnin, V. Callegari, S. Mátéfi-Tempfli, M. Mátéfi-Tempfli, K. Glinel, A. M. Jonas, and S. Demoustier-Champagne Web Release Date: Thu, 21 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm8005402
Lingrong Gu, Pengju G. Luo, Haifang Wang, Mohammed J. Meziani, Yi Lin, L. Monica Veca, Li Cao, Fushen Lu, Xin Wang, Robert A. Quinn, Wei Wang, Puyu Zhang, Sebastian Lacher, and Ya-Ping Sun Web Release Date: Wed, 20 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800395e
Thierry Lefèvre, Simon Boudreault, Conrad Cloutier, and Michel Pézolet Web Release Date: Fri, 15 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800390j
Satyajeet S. Ojha, Derrick R. Stevens, Torissa J. Hoffman, Kelly Stano, Rebecca Klossner, Mary C. Scott, Wendy Krause, Laura I. Clarke, and Russell E. Gorga Web Release Date: Fri, 15 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800551q
Gloria Fernandez-Lorente, Cesar A. Godoy, Adriano A. Mendes, Fernando Lopez-Gallego, Valeria Grazu, Blanca de las Rivas, Jose M. Palomo, Juan Hermoso, Roberto Fernandez-Lafuente, and Jose M. Guisan Web Release Date: Fri, 15 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800609g
Luis Rojo, Jose. M. Barcenilla, Blanca Vázquez, Ramón González, and Julio San Román Web Release Date: Fri, 15 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800570u
Nadja Nijenhuis, Daisuke Mizuno, Christoph F. Schmidt, Hans Vink, and Jos A. E. Spaan Web Release Date: Thu, 14 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800381z
Jun Hu, Lihong Huang, Xiuli Zhuang, Peibiao Zhang, Le Lang, Xuesi Chen, Yen Wei, and Xiabin Jing Web Release Date: Wed, 13 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800705t
Background:
Many studies have examined rules governing two aspects of protein structures: short segments and proteins' structural domains. Nevertheless, the organization and nature of the conformational space of segments with intermediate length between short segments and domains remain unclear. Conformational spaces of intermediate length segments probably differ from those of short segments. We investigated the identification and characterization of the boundary(s) between peptide-like (short segment) and protein-like (long segment) distributions. We generated ensembles embedded in globular proteins comprising segments 10–50 residues long. We explored the relationships between the conformational distribution of segments and their lengths, and also protein structural classes using principal component analysis based on the intra-segment Cα-Cα atomic distances.
Results:
Our statistical analyses of segment conformations and length revealed critical dual transitions in their conformational distribution with segments derived from all four structural classes. Dual transitions were identified with the intermediate phase between the short segments and domains. Consequently, protein segment universes were categorized. i) Short segments (10–22 residues) showed a distribution with a high frequency of secondary structure clusters. ii) Medium segments (23–26 residues) showed a distribution corresponding to an intermediate state of transitions. iii) Long segments (27–50 residues) showed a distribution converging on one huge cluster containing compact conformations with a smaller radius of gyration. This distribution reflects the protein structures' organization and protein domains' origin. Three major conformational components (radius of gyration, structural symmetry with respect to the N-terminal and C-terminal halves, and single-turn/two-turn structure) well define most of the segment universes. Furthermore, we identified several conformational components that were unique to each structural class. Those characteristics suggest that protein segment conformation is described by compositions of the three common structural variables with large contributions and specific structural variables with small contributions.
Conclusion:
The present results of the analyses of four protein structural classes show the universal role of three major components as segment conformational descriptors. The obtained perspectives of distribution changes related to the segment lengths using the three key components suggest both the adequacy and the possibility of further progress on the prediction strategies used in the recent de novo structure-prediction methods.
Background:
Several different methods for contact prediction succeeded within the Sixth Critical Assessment of Techniques for Protein Structure Prediction (CASP6). The most relevant were non-local contact predictions for targets from the most difficult categories: fold recognition-analogy and new fold. Such contacts could provide valuable structural information in case a template structure cannot be found in the PDB.
Results:
We described comprehensive tests of the effectiveness of contact data in various aspects of de novo modeling with CABS, an algorithm which was used successfully in CASP6 by the Kolinski-Bujnicki group. We used the predicted contacts in a simple scoring function for the post-simulation ranking of protein models and as a soft bias in the folding simulations and in the fold-refinement procedure. The latter approach turned out to be the most successful. The CABS force field used in the Replica Exchange Monte Carlo simulations cooperated with the true contacts and discriminated the false ones, which resulted in an improvement of the majority of Kolinski-Bujnicki's protein models. In the modeling we tested different sets of predicted contact data submitted to the CASP6 server. According to our results, the best performing were the contacts with the accuracy balanced with the coverage, obtained either from the best two predictors only or by a consensus from as many predictors as possible.
Conclusion:
Our tests have shown that theoretically predicted contacts can be very beneficial for protein structure prediction. Depending on the protein modeling method, a contact data set applied should be prepared with differently balanced coverage and accuracy of predicted contacts. Namely, high coverage of contact data is important for the model ranking and high accuracy for the folding simulations.
Background:
There are considerable differences between bacterial and mammalian glycans. In contrast to most eukaryotic carbohydrates, bacterial glycans are often composed of repeating units with diverse functions ranging from structural reinforcement to adhesion, colonization and camouflage. Since bacterial glycans are typically displayed at the cell surface, they can interact with the environment and, therefore, have significant biomedical importance.
Results:
The sequence characteristics of glycans (monosaccharide composition, modifications, and linkage patterns) for the higher bacterial taxonomic classes have been examined and compared with the data for mammals, with both similarities and unique features becoming evident. Compared to mammalian glycans, the bacterial glycans deposited in the current databases have a more than ten-fold greater diversity at the monosaccharide level, and the disaccharide pattern space is approximately nine times larger. Specific bacterial subclasses exhibit characteristic glycans which can be distinguished on the basis of distinctive structural features or sequence properties.
Conclusions:
For the first time a systematic database analysis of the bacterial glycome has been performed. This study summarizes the current knowledge of bacterial glycan architecture and diversity and reveals putative targets for the rational design and development of therapeutic intervention strategies by comparing bacterial and mammalian glycans.
Silke Berski, Jeroen van Bergeijk, David Schwarzer, Yvonne Stark, Cornelia Kasper, Thomas Scheper, Claudia Grothe, Rita Gerardy-Schahn, Andreas Kirschning, and Gerald Dräger Web Release Date: Sat, 9 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800327s
H. Kokkonen, C. Cassinelli, R. Verhoef, M. Morra, H. A. Schols, and J. Tuukkanen Web Release Date: Tue, 5 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800356b
Lu Chen, Hernán R. Rengifo, Cristian Grigoras, Xiaoxu Li, Zengmin Li, Jingyue Ju, and Jeffrey T. Koberstein Web Release Date: Tue, 5 Aug 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800258g
Background:
Automatic protein modelling pipelines are becoming ever more accurate; this has come hand in hand with an increasingly complicated interplay between all components involved. Nevertheless, there are still potential improvements to be made in template selection, refinement and protein model selection.
Results:
In the context of an automatic modelling pipeline, we analysed each step separately, revealing several non-intuitive trends and explored a new strategy for protein conformation sampling using Genetic Algorithms (GA). We apply the concept of alternating evolutionary pressure (AEP), i.e. intermediate rounds within the GA runs where unrestrained, linear growth of the model populations is allowed.
Conclusion:
This approach improves the overall performance of the GA by allowing models to overcome local energy barriers. AEP enabled the selection of the best models in 40% of all targets; compared to 25% for a normal GA.
Jennifer A. Hornemann, Anna A. Lysova, Sarah L. Codd, Joseph D. Seymour, Scott C. Busse, Philip S. Stewart, and Jennifer R. Brown Web Release Date: Wed, 30 Jul 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800269h
M. A. Jafar Mazumder, Feng Shen, Nicholas A. D. Burke, Murray A. Potter, and Harald D. H. Stöver Web Release Date: Wed, 30 Jul 2008 00:00:00 EDT (Article) DOI: 10.1021/bm800580c
Background:
In search of new antifungal targets of potential interest for pharmaceutical companies, we initiated a comparative genomics study to identify the most promising protein-coding genes in fungal genomes. One criterion was the protein sequence conservation between reference pathogenic genomes. A second criterion was that the corresponding gene in Saccharomyces cerevisiae should be essential. Since thiamine pyrophosphate is an essential product involved in a variety of metabolic pathways, proteins responsible for its production satisfied these two criteria.
Results:
We report the enzymatic characterization and the crystallographic structure of the Candida albicans Thiamine pyrophosphokinase. The protein was co-crystallized with thiamine or thiamine-PNP.
Conclusion:
The presence of an inorganic phosphate in the crystallographic structure opposite the known AMP binding site relative to the thiamine moiety suggests that a second AMP molecule could be accommodated in the C. albicans structure. Together with the crystallographic structures of the enzyme/substrate complexes this suggests the existence of a secondary, less specific, nucleotide binding site in the Candida albicans thiamine pyrophosphokinase which could transiently serve during the release or the binding of ATP. The structures also highlight a conserved Glutamine residue (Q138) which could interact with the ATP α-phosphate and act as gatekeeper. Finally, the TPK/Thiamine-PNP complex is consistent with a one step mechanism of pyrophosphorylation.
Jianguo Sun, Stefan V. Graeter, Lin Yu, Shifeng Duan, Joachim P. Spatz, and Jiandong Ding Web Release Date: Wed, 23 Jul 2008 00:00:00 EDT (Communication) DOI: 10.1021/bm800477s
Background:
Urate oxidase (EC 1.7.3.3 or UOX) catalyzes the conversion of uric acid and gaseous molecular oxygen to 5-hydroxyisourate and hydrogen peroxide, in the absence of cofactor or particular metal cation. The functional enzyme is a homo-tetramer with four active sites located at dimeric interfaces.
Results:
The catalytic mechanism was investigated through a ternary complex formed between the enzyme, uric acid, and cyanide that stabilizes an intermediate state of the reaction. When uric acid is replaced by a competitive inhibitor, no complex with cyanide is formed.
Conclusion:
The X-ray structure of this compulsory ternary complex led to a number of mechanistic evidences that support a sequential mechanism in which the two reagents, dioxygen and a water molecule, process through a common site located 3.3 Ã… above the mean plane of the ligand. This site is built by the side chains of Asn 254, and Thr 57, two conserved residues belonging to two different subunits of the homo-tetramer. The absence of a ternary complex between the enzyme, a competitive inhibitor, and cyanide suggests that cyanide inhibits the hydroxylation step of the reaction, after the initial formation of a hydroperoxyde type intermediate.
Background:
Although multiple templates are frequently used in comparative modeling, the effect of inclusion of additional template(s) on model accuracy (when compared to that of corresponding single-template based models) is not clear. To address this, we systematically analyze two-template models, the simplest case of multiple-template modeling. For an existing target-template pair (single-template modeling), a two-template based model of the target sequence is constructed by including an additional template without changing the original alignment to measure the effect of the second template on model accuracy.
Results:
Even though in a large number of cases a two-template model showed higher accuracy than the corresponding one-template model, over the entire dataset only a marginal improvement was observed on average, as there were many cases where no change or the reverse change was observed. The increase in accuracy due to the structural complementarity of the templates increases at higher alignment accuracies. The combination of templates showing the highest potential for improvement is that where both templates share similar and low (less than 30%) sequence identity with the target, as well as low sequence identity with each other. The structural similarity between the templates also helps in identifying template combinations having a higher chance of resulting in an improved model.
Conclusion:
Inclusion of additional template(s) does not necessarily improve model quality, but there are distinct combinations of the two templates, which can be selected a priori, that tend to show improvement in model quality over the single template model. The benefit derived from the structural complementarity is dependent on the accuracy of the modeling alignment. The study helps to explain the observation that a careful selection of templates together with an accurate target:template alignment are necessary to the benefit from using multiple templates in comparative modeling and provides guidelines to maximize the benefit from using multiple templates. This enables formulation of simple template selection rules to rank targets of a protein family in the context of structural genomics.
Background:
The Ambiguous Restraints for Iterative Assignment (ARIA) approach is widely used for NMR structure determination. It is based on simultaneously calculating structures and assigning NOE through an iterative protocol. The final solution consists of a set of conformers and a list of most probable assignments for the input NOE peak list.
Results:
ARIA was extended with a series of graphical tools to facilitate a detailed analysis of the intermediate and final results of the ARIA protocol. These additional features provide (i) an interactive contact map, serving as a tool for the analysis of assignments, and (ii) graphical representations of structure quality scores and restraint statistics. The interactive contact map between residues can be clicked to obtain information about the restraints and their contributions. Profiles of quality scores are plotted along the protein sequence, and contact maps provide information of the agreement with the data on a residue pair level.
Conclusion:
The graphical tools and outputs described here significantly extend the validation and analysis possibilities of NOE assignments given by ARIA as well as the analysis of the quality of the final structure ensemble. These tools are included in the latest version of ARIA, which is available at http://aria.pasteur.fr. The Web site also contains an installation guide, a user manual and example calculations.
Background:
Recently, we reported a unique approach to preserve the activity of some proteins in the presence of the denaturing agent, Sodium Dodecyl Sulfate (SDS). This was made possible by addition of the amphipathic solvent 2,4-Methyl-2-PentaneDiol (MPD), used as protecting but also as refolding agent for these proteins. Although the persistence of the protein activity in the SDS/MPD mixture was clearly established, preservation of their structure was only speculative until now.
Results:
In this paper, a detailed X-ray study addresses the pending question. Crystals of hen egg-white lysozyme were grown for the first time in the presence of MPD and denaturing concentrations of SDS. Depending on crystallization conditions, tetragonal crystals in complex with either SDS or MPD were collected. The conformation of both structures was very similar to the native lysozyme and the obtained complexes of SDS-lysozyme and MPD-lysozyme give some insights in the interplay of protein-SDS and protein-MPD interactions.
Conclusion:
This study clearly established the preservation of the enzyme structure in a SDS/MPD mixture. It is hypothesized that high concentrations of MPD would change the properties of SDS and lower or avoid interactions between the denaturant and the protein. These structural data therefore support the hypothesis that MPD avoids disruption of the enzyme structure by SDS and can protect proteins from SDS denaturation.
