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Biomedical subjects

Jakub Pas

Publications and source records attributed to Jakub Pas.

12 recordsLinked to original sources
PubMed2006

Leadzyme formed in vivo interferes with tobacco mosaic virus infection in Nicotiana tabacum.

We developed a new method for inhibiting tobacco mosaic virus infection in tobacco plants based on specific RNA hydrolysis induced by a leadzyme. We identified a leadzyme substrate target sequence in genomic tobacco mosaic virus RNA and designed a 16-mer oligoribonucleotide capable of forming a specific leadzyme motif with a five-nucleotide catalytic loop. The synthetic 16-mer RNA was applied with nontoxic, catalytic amount of lead to infected tobacco leaves. We observed inhibition of tobacco mosaic virus infection in tobacco leaves in vivo due to specific tobacco mosaic virus RNA cleavage effected by leadzyme. A significant reduction in tobacco mosaic virus accumulation was observed even when the leadzyme was applied up to 2 h after inoculation of leaves with tobacco mosaic virus. This process, called leadzyme interference, is determined by specific recognition and cleavage of the target site by the RNA catalytic strand in the presence of Pb(2+).

Anti-Infective Agents↗
PubMed2006

Analysis of structure and function of tenascin-C.

Tenascin-C is a multidomain large extracellular matrix glycoprotein composed of six monomers. The size of tenascin-C monomers (180-250 kDa) varies as a result of an alternative splicing of the fibronectin repeats at the pre-mRNA level. For the first time we applied bioinformatic and molecular modeling procedures, for detailed analysis of the organization of tenascin-C and we performed bioinformatic analysis of tenascin-C gene. We detected the presence of heat shock protein 33 in the tenascin-C N-terminal domain that may suggest its role in the protein-protein interactions and stress response. The number of fibronectin type III-like repeats and epidermal growth factor-like repeats were corrected to 15 and 14, respectively. Using polyactylamide gel electophoresis, RT/PCR analysis and microarrays data, we showed the higher level of tenascin-C in the human tumor tissues: brain, intestine and breast. These results suggested a new role of tenascin-C as the potential tumor marker and drug target.

Alternative Splicing↗
PubMed2004

Lead toxicity through the leadzyme.

Lead is one of the most dangerous toxic agents for all living organisms. In humans, elevated levels of lead have been linked to a number of disorders for which various molecular mechanisms have been proposed. However, none of them has been fully understood. It has also been known for several years that at micromolar concentrations lead can bind a unique RNA motif and catalyze a site-specific hydrolysis of the polyribonucleotide chain. This motif, called leadzyme, may be one of the major targets for lead within the cell, and it can cleave various cellular RNAs. A search of GenBank revealed the sequences that can potentially fold into the structure containing the leadzyme motif and that they are rather common in eukaryotic genomes. We found that the domain occurs with a high frequency in human mRNA sequences. Thus, the leadzyme nucleolytic properties should be considered as a possible mechanism for destruction of RNA within a cell. In particular, targeting of the RNA scaffold of ribosomes or spliceosomes may explain lead-mediated toxicity leading to cell death.

Humans↗
PubMed2004

Structure prediction, evolution and ligand interaction of CHASE domain.

Cytokinins are plant hormones involved in the essential processes of plant growth and development. They bind with receptors known as CRE1/WOL/AHK4, AHK2, and AHK3, which possess histidine kinase activity. Recently, the sensor domain cyclases/histidine kinases associated sensory extracellular (CHASE) was identified in those proteins but little is known about its structure and interaction with ligands. Distant homology detection methods developed in our laboratory and molecular phylogeny enabled the prediction of the structure of the CHASE domain as similar to the photoactive yellow protein-like sensor domain. We have identified the active site pocket and amino acids that are involved in receptor-ligand interactions. We also show that fold evolution of cytokinin receptors is very important for a full understanding of the signal transduction mechanism in plants.

Amino Acid Sequence↗
PubMed2004

Ligand.Info small-molecule Meta-Database.

Ligand.Info is a compilation of various publicly available databases of small molecules. The total size of the Meta-Database is over 1 million entries. The compound records contain calculated three-dimensional coordinates and sometimes information about biological activity. Some molecules have information about FDA drug approving status or about anti-HIV activity. Meta-Database can be downloaded from the http://Ligand.Info web page. The database can also be screened using a Java-based tool. The tool can interactively cluster sets of molecules on the user side and automatically download similar molecules from the server. The application requires the Java Runtime Environment 1.4 or higher, which can be automatically downloaded from Sun Microsystems or Apple Computer and installed during the first use of Ligand.Info on desktop systems, which support Java (Ms Windows, Mac OS, Solaris, and Linux). The Ligand.Info Meta-Database can be used for virtual high-throughput screening of new potential drugs. Presented examples showed that using a known antiviral drug as query the system was able to find others antiviral drugs and inhibitors.

Databases, Genetic↗
PubMed2004

Comparison of proteins based on segments structural similarity.

We present here a simple method for fast and accurate comparison of proteins using their structures. The algorithm is based on structural alignment of segments of Calpha chains (with size of 99 or 199 residues). The method is optimized in terms of speed and accuracy. We test it on 97 representative proteins with the similarity measure based on the SCOP classification. We compare our algorithm with the LGscore2 automatic method. Our method has the same accuracy as the LGscore2 algorithm with much faster processing of the whole test set, which is promising. A second test is done using the ToolShop structure prediction evaluation program and shows that our tool is on average slightly less sensitive than the DALI server. Both algorithms give a similar number of correct models, however, the final alignment quality is better in the case of DALI. Our method was implemented under the name 3D-Hit as a web server at http://3dhit.bioinfo.pl/ free for academic use, with a weekly updated database containing a set of 5000 structures from the Protein Data Bank with non-homologous sequences.

Algorithms↗
PubMed2003

ORFeus: Detection of distant homology using sequence profiles and predicted secondary structure.

ORFeus is a fully automated, sensitive protein sequence similarity search server available to the academic community via the Structure Prediction Meta Server (http://BioInfo.PL/Meta/). The goal of the development of ORFeus was to increase the sensitivity of the detection of distantly related protein families. Predicted secondary structure information was added to the information about sequence conservation and variability, a technique known from hybrid threading approaches. The accuracy of the meta profiles created this way is compared with profiles containing only sequence information and with the standard approach of aligning a single sequence with a profile. Additionally, the alignment of meta profiles is more sensitive in detecting remote homology between protein families than if aligning two sequence-only profiles or if aligning a profile with a sequence. The specificity of the alignment score is improved in the lower specificity range compared with the robust sequence-only profiles.

Algorithms↗
PubMed2003

Ligand-Info, searching for similar small compounds using index profiles.

MOTIVATION: The Ligand-Info system is based on the assumption that small molecules with similar structure have similar functional (binding) properties. The developed system enables a fast and sensitive index based search for similar compounds in large databases. Index profiles, constructed by averaging indexes of related molecules are used to increase the specificity of the search. The utilization of index profiles helps to focus on frequent, common features of a family of compounds. RESULTS: A Java-based tool for clustering and scanning of small molecules has been created. The tool can interactively cluster sets of molecules and create index profiles on the user side and automatically download similar molecules from a databases of 250 000 compounds. The results of the application of index profiles demonstrate that the profile based search strategy can increase the quality of the selection process. AVAILABILITY: The system is available at http://Ligand.Info. The application requires the Java Runtime Environment 1.4, which can be automatically installed during the first use on desktop systems, which support it. A standalone version of the program is available from the authors upon request.

Binding Sites↗
PubMed2003

Molecular phylogenetics of the RrmJ/fibrillarin superfamily of ribose 2'-O-methyltransferases.

Recent analyses identified a putative catalytic tetrad K-D-K-E common to several families of site-specific methyltransferases (MTases) that modify 2'-hydroxyl groups of ribose in mRNA, rRNA and tRNA (designated the RrmJ class after one of the structurally characterized members; 1eiz in Protein Data Bank) [Genome Biol. 2(9) (2001) 38]. Subsequently, three residues of the tetrad (K-D-K) were shown to be essential for catalysis in RrmJ [J. Biol. Chem. 277 (2002) 41978]. Here, we report identification of a similar conserved tetrad (K-D-K-H) in the family of snoRNA-guided ribose 2'-O-MTases related to fibrillarin (represented by the Mj0697 protein structure; 1fbn in PDB). The corresponding functional groups of putative catalytic tetrads of RrmJ and Mj0697 may be superimposed in space. However, one of the invariant residues (K(164) in RrmJ and K(179) in Mj0697) is observed in two distinct locations in the primary sequence, suggesting an interesting case of 'migration' of the conserved side chain within the framework of the active site. RrmJ and Mj0697 sequences were used as starting points to carry out comprehensive sequence database searches, resulting in identification of a similar conserved tetrad (and hence, prediction of a ribose 2'-O-specificity) in several families of putative MTases, including TlyA hemolysins, novel proteins from Trypanosoma, and large multidomain proteins from Flaviviriruses, Nidoviruses, and Alphaviruses. The results of our analysis of phylogenetic relationships in the RrmJ/fibrillarin superfamily provide insight into the evolution of site-specific and snoRNA-guided ribose 2'-O-MTases from a common ancestor.

Amino Acid Sequence↗
PubMed2003

Application of 3D-Jury, GRDB, and Verify3D in fold recognition.

In CASP5, the BioInfo.PL group has used the structure prediction Meta Server and the associated newly developed flexible meta-predictor, called 3D-Jury, as the main structure prediction tools. The most important feature of the meta-predictor is a high (86%) correlation between the reported confidence score and the quality of the selected model. The Gene Relational Database (GRDB) was used to confirm the fold recognition results by selecting distant homologues and subsequent structure prediction with the Meta Server. A fragment-splicing procedure was performed as a final processing step with large fragments extracted from selected models using model quality control provided by Verify3D. The comparison of submitted models with the native structure conducted after the CASP meeting showed that the GRDB-supported structure prediction led to a satisfactory template fold selection, whereas the fragment-splicing procedure must be improved in the future.

Amino Acid Sequence↗