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18 papers found.
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Kinetic barriers in the isomerization of substituted ureas: implications for computer-aided drug design

Klaus R. Liedl 0 1 0 Institute of General, Inorganic and Theoretical Chemistry, Faculty of Chemistry and Pharmacy, University of Innsbruck , Innrain 82, 6020 Innsbruck , Austria 1 & Julian E. Fuchs Urea

Entropy in specificity and thermodynamics of binding

Klaus R Liedl 0 0 Leopold-Franzens-University Innsbruck, Faculty of Chemistry and Pharmacy, Centre for Chemistry and Biomedicine (CCB) , Innrain 82, 6020 Innsbruck , Austria W. Jeffery Hurst, The

Characterizing Protease Specificity: How Many Substrates Do We Need?

Calculation of cleavage entropies allows to quantify, map and compare protease substrate specificity by an information entropy based approach. The metric intrinsically depends on the number of experimentally determined substrates (data points). Thus a statistical analysis of its numerical stability is crucial to estimate the systematic error made by estimating specificity based...

Dynamics Govern Specificity of a Protein-Protein Interface: Substrate Recognition by Thrombin

Austrian Academy of Sciences for a DOC-fellowship at the Institute of General, Inorganic and Theoretical Chemistry at University of Innsbruck. Klaus R. Liedl gratefully acknowledges the Austrian Science Fund

FAH Domain Containing Protein 1 (FAHD-1) Is Required for Mitochondrial Function and Locomotion Activity in C. elegans

The fumarylacetoacetate hydrolase (FAH) protein superfamily of metabolic enzymes comprises a diverse set of enzymatic functions, including ß-diketone hydrolases, decarboxylases, and isomerases. Of note, the FAH superfamily includes many prokaryotic members with very distinct functions that lack homologs in eukaryotes. A prokaryotic member of the FAH superfamily, referred to as...

Substrate-Driven Mapping of the Degradome by Comparison of Sequence Logos

Sequence logos are frequently used to illustrate substrate preferences and specificity of proteases. Here, we employed the compiled substrates of the MEROPS database to introduce a novel metric for comparison of protease substrate preferences. The constructed similarity matrix of 62 proteases can be used to intuitively visualize similarities in protease substrate readout via...

A Cross-Reactive Human Single-Chain Antibody for Detection of Major Fish Allergens, Parvalbumins, and Identification of a Major IgE-Binding Epitope

Fish allergy is associated with moderate to severe IgE-mediated reactions to the calcium binding parvalbumins present in fish muscle. Allergy to multiple fish species is caused by parvalbumin-specific cross-reactive IgE recognizing conserved epitopes. In this study, we aimed to produce cross-reactive single chain variable fragment (scFv) antibodies for the detection of...

Qualitative prediction of blood–brain barrier permeability on a large and refined dataset

The prediction of blood–brain barrier permeation is vitally important for the optimization of drugs targeting the central nervous system as well as for avoiding side effects of peripheral drugs. Following a previously proposed model on blood–brain barrier penetration, we calculated the cross-sectional area perpendicular to the amphiphilic axis. We obtained a high correlation...

Effects of Pooling Samples on the Performance of Classification Algorithms: A Comparative Study

A pooling design can be used as a powerful strategy to compensate for limited amounts of samples or high biological variation. In this paper, we perform a comparative study to model and quantify the effects of virtual pooling on the performance of the widely applied classifiers, support vector machines (SVMs), random forest (RF), k-nearest neighbors (k-NN), penalized logistic...

A gatekeeper helix determines the substrate specificity of Sjögren–Larsson Syndrome enzyme fatty aldehyde dehydrogenase

Innsbruck, Innrain 80-82, 6020 Innsbruck, AustriaChristoph Kreutz, Thomas Mueller, Klaus R. Liedl & Bernhard KräutlerMRC National Institute for Medical Research, the Ridgeway, Mill Hill, London NW7 1AA ... • PubMed • Google ScholarSearch for Georg Golderer in:Nature Research journals • PubMed • Google ScholarSearch for Klaus R. Liedl in:Nature Research journals • PubMed • Google ScholarSearch for Markus Ralser

Cleavage Entropy as Quantitative Measure of Protease Specificity

A purely information theory-guided approach to quantitatively characterize protease specificity is established. We calculate an entropy value for each protease subpocket based on sequences of cleaved substrates extracted from the MEROPS database. We compare our results with known subpocket specificity profiles for individual proteases and protease groups (e.g. serine proteases...

Dynamic Regulation of Phenylalanine Hydroxylase by Simulated Redox Manipulation

Recent clinical studies revealed increased phenylalanine levels and phenylalanine to tyrosine ratios in patients suffering from infection, inflammation and general immune activity. These data implicated down-regulation of activity of phenylalanine hydroxylase by oxidative stress upon in vivo immune activation. Though the structural damage of oxidative stress is expected to be...

The Impact of Nitration on the Structure and Immunogenicity of the Major Birch Pollen Allergen Bet v 1.0101

Allergy prevalence has increased in industrialized countries. One contributing factor could be pollution, which can cause nitration of allergens exogenously (in the air) or endogenously (in inflamed lung tissue). We investigated the impact of nitration on both the structural and immunological behavior of the major birch pollen allergen Bet v 1.0101 to determine whether nitration...

Identification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation

Background Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial...

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy...

Cooperative effects on the formation of intercalation sites

Daunomycin is one of the most important agents used in anticancer chemotherapy. It interacts with DNA through intercalation of its planar chromophore between successive base pairs. The effect of intercalation on structure, dynamics and energetics is the topic of a wealth of scientific studies. In the present study, we report a computational examination of the energetics of the...

Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation

The structure of human Janus kinase 2 (JAK2) comprising the two C-terminal domains (JH1 and JH2) was predicted by application of homology modelling techniques. JH1 and JH2 represent the tyrosine kinase and tyrosine kinase-like domains, respectively, and are crucial for function and regulation of the protein. A comparison between the structures of the two domains is made and...

Exocyclic groups in the minor groove influence the backbone conformation of DNA

Exocyclic groups in the minor groove of DNA modulate the affinity and positioning of nucleic acids to the histone protein. The addition of exocyclic groups decreases the formation of this protein–DNA complex, while their removal increases nucleosome formation. On the other hand, recent theoretical results show a strong correlation between the BI/BII phosphate backbone...