36 research outputs found
Identifying allosteric fluctuation transitions between different protein conformational states as applied to Cyclin Dependent Kinase 2
BACKGROUND: The mechanisms underlying protein function and associated conformational change are dominated by a series of local entropy fluctuations affecting the global structure yet are mediated by only a few key residues. Transitional Dynamic Analysis (TDA) is a new method to detect these changes in local protein flexibility between different conformations arising from, for example, ligand binding. Additionally, Positional Impact Vertex for Entropy Transfer (PIVET) uses TDA to identify important residue contact changes that have a large impact on global fluctuation. We demonstrate the utility of these methods for Cyclin-dependent kinase 2 (CDK2), a system with crystal structures of this protein in multiple functionally relevant conformations and experimental data revealing the importance of local fluctuation changes for protein function. RESULTS: TDA and PIVET successfully identified select residues that are responsible for conformation specific regional fluctuation in the activation cycle of Cyclin Dependent Kinase 2 (CDK2). The detected local changes in protein flexibility have been experimentally confirmed to be essential for the regulation and function of the kinase. The methodologies also highlighted possible errors in previous molecular dynamic simulations that need to be resolved in order to understand this key player in cell cycle regulation. Finally, the use of entropy compensation as a possible allosteric mechanism for protein function is reported for CDK2. CONCLUSION: The methodologies embodied in TDA and PIVET provide a quick approach to identify local fluctuation change important for protein function and residue contacts that contributes to these changes. Further, these approaches can be used to check for possible errors in protein dynamic simulations and have the potential to facilitate a better understanding of the contribution of entropy to protein allostery and function
A physicochemical descriptor-based scoring scheme for effective and rapid filtering of kinase-like chemical space
<p>Abstract</p> <p>Background</p> <p>The current chemical space of known small molecules is estimated to exceed 10<sup>60 </sup>structures. Though the largest physical compound repositories contain only a few tens of millions of unique compounds, virtual screening of databases of this size is still difficult. In recent years, the application of physicochemical descriptor-based profiling, such as Lipinski's rule-of-five for drug-likeness and Oprea's criteria of lead-likeness, as early stage filters in drug discovery has gained widespread acceptance. In the current study, we outline a kinase-likeness scoring function based on known kinase inhibitors.</p> <p>Results</p> <p>The method employs a collection of 22,615 known kinase inhibitors from the ChEMBL database. A kinase-likeness score is computed using statistical analysis of nine key physicochemical descriptors for these inhibitors. Based on this score, the kinase-likeness of four publicly and commercially available databases, i.e., National Cancer Institute database (NCI), the Natural Products database (NPD), the National Institute of Health's Molecular Libraries Small Molecule Repository (MLSMR), and the World Drug Index (WDI) database, is analyzed. Three of these databases, i.e., NCI, NPD, and MLSMR are frequently used in the virtual screening of kinase inhibitors, while the fourth WDI database is for comparison since it covers a wide range of known chemical space. Based on the kinase-likeness score, a kinase-focused library is also developed and tested against three different kinase targets selected from three different branches of the human kinome tree.</p> <p>Conclusions</p> <p>Our proposed methodology is one of the first that explores how the narrow chemical space of kinase inhibitors and its relevant physicochemical information can be utilized to build kinase-focused libraries and prioritize pre-existing compound databases for screening. We have shown that focused libraries generated by filtering compounds using the kinase-likeness score have, on average, better docking scores than an equivalent number of randomly selected compounds. Beyond library design, our findings also impact the broader efforts to identify kinase inhibitors by screening pre-existing compound libraries. Currently, the NCI library is the most commonly used database for screening kinase inhibitors. Our research suggests that other libraries, such as MLSMR, are more kinase-like and should be given priority in kinase screenings.</p
A Novel Protein Kinase-Like Domain in a Selenoprotein, Widespread in the Tree of Life
Selenoproteins serve important functions in many organisms, usually providing essential oxidoreductase enzymatic activity, often for defense against toxic xenobiotic substances. Most eukaryotic genomes possess a small number of these proteins, usually not more than 20. Selenoproteins belong to various structural classes, often related to oxidoreductase function, yet a few of them are completely uncharacterised
An integrated computational-experimental approach reveals Yersinia pestis genes essential across a narrow or a broad range of environmental conditions
Cesium and strontium tolerant Arthrobacter sp. strain KMSZP6 isolated from a pristine uranium ore deposit
Distribuição e alimentação de duas espécies simpátricas de piranhas Serrasalmus maculatus e Pygocentrus nattereri (Characidae, Serrasalminae) do rio Ibicuí, Rio Grande do Sul, Brasil Distribution and feeding of two sympatric species of piranhas Serrasalmus maculatus and Pygocentrus nattereri (Characidae, Serrasalminae) of the Ibicuí river, State of Rio Grande do Sul, Brazil
Duas espécies de piranhas ocorrem no rio Ibicuí, um dos principais afluentes do rio Uruguai. Com o objetivo de analisar a distribuição e a alimentação destas espécies, foram realizadas coletas de dezembro de 1999 a janeiro de 2002, utilizando-se diferentes artes de pesca em três pontos do rio, sendo que cada ponto foi amostrado em dois ambientes (lêntico e lótico). Foram capturados 203 indivíduos de Serrasalmus maculatus Kner, 1858 e 86 de Pygocentrus nattereri Kner, 1858, sendo que a maior captura de ambas as espécies ocorreu no ambiente lêntico e próximo ao rio Uruguai, onde P. nattereri parece estar mais concentrada. O número de exemplares capturados por horário não apresentou variações significativas em P. nattereri enquanto que S. maculatus apresentou a maior captura na revisão da meia-noite. Juvenis de S. maculatus (2-4 cm de comprimento padrão) consumiram preferencialmente nadadeiras e insetos. Nas demais classes de tamanho de ambas as espécies, restos de peixes foi o alimento predominante, havendo sobreposição alimentar intra e interespecífica nas maiores classes (8-16 cm e >16 cm de comprimento padrão). Não foram constatadas diferenças no índice de repleção entre os horários e os ambientes para as duas espécies.<br>Two species of piranhas occur in the Ibicuí River, one of the main tributaries of the Uruguay River in southern Brazil, Serrasalmus maculatus Kner, 1858 and Pygocentrus nattereri Kner, 1858. In order to analyze the distribution and feeding habits of these species we conducted collecting expeditions from December 1999 to January 2002, using a variety of fishing gears in three sites along the river, both in lentic and lotic habitats. A total of 203 individuals of S. maculatus and 86 of P. nattereri were caught, mostly in lentic habitats and closer to the Uruguay River, were P. nattereri seems to be more concentrated. The number of individuals captured at different times did not show variation in P. nattereri while the number of S. maculatus captured at mid-night was the highest. Young S. maculatus (2-4 cm standard length) fed mainly on fish fins and insects. Fish was the predominant item in remaining size classes for both species, with intra- and inter-specific overlap in larger classes (8-16 cm and >16 cm standard length). No differences in the repletion index between day time or habitats, were observed for the two species