Search results for "structural"
showing 10 items of 5047 documents
Innovative Strategies to Develop Chemical Categories Using a Combination of Structural and Toxicological Properties.
2016
Interest is increasing in the development of non-animal methods for toxicological evaluations. These methods are however, particularly challenging for complex toxicological endpoints such as repeated dose toxicity. European Legislation, e.g., the European Union's Cosmetic Directive and REACH, demands the use of alternative methods. Frameworks, such as the Read-across Assessment Framework or the Adverse Outcome Pathway Knowledge Base, support the development of these methods. The aim of the project presented in this publication was to develop substance categories for a read-across with complex endpoints of toxicity based on existing databases. The basic conceptual approach was to combine str…
Rpb1 foot mutations demonstrate a major role of Rpb4 in mRNA stability during stress situations in yeast.
2016
The RPB1 mutants in the foot region of RNA polymerase II affect the assembly of the complex by altering the correct association of both the Rpb6 and the Rpb4/7 dimer. Assembly defects alter both transcriptional activity as well as the amount of enzyme associated with genes. Here, we show that the global transcriptional analysis of foot mutants reveals the activation of an environmental stress response (ESR), which occurs at a permissive temperature under optimal growth conditions. Our data indicate that the ESR that occurs in foot mutants depends mostly on a global post-transcriptional regulation mechanism which, in turn, depends on Rpb4-mRNA imprinting. Under optimal growth conditions, we …
Mechanism and biological role of Dnmt2 in Nucleic Acid Methylation
2016
ABSTRACT A group of homologous nucleic acid modification enzymes called Dnmt2, Trdmt1, Pmt1, DnmA, and Ehmet in different model organisms catalyze the transfer of a methyl group from the cofactor S-adenosyl-methionine (SAM) to the carbon-5 of cytosine residues. Originally considered as DNA MTases, these enzymes were shown to be tRNA methyltransferases about a decade ago. Between the presumed involvement in DNA modification-related epigenetics, and the recent foray into the RNA modification field, significant progress has characterized Dnmt2-related research. Here, we review this progress in its diverse facets including molecular evolution, structural biology, biochemistry, chemical biology,…
Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen, a new dopaminergic agent
2017
Abstract The drug development process strives to predict metabolic fate of a drug candidate, together with its uptake in major organs, whether they act as target, deposit or metabolism sites, to the aim of establish a relationship between the pharmacodynamics and the pharmacokinetics and highlight the potential toxicity of the drug candidate. The present study was aimed at evaluating the in vivo uptake of 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) − a new dopaminergic neurotransmission modulator, in target and non-target organs of animal subjects and integrating these data with SMARTCyp results, an in silico method that predicts the sites of cytochrome P450-m…
Modulation of protein synthesis and degradation maintains proteostasis during yeast growth at different temperatures
2016
To understand how cells regulate each step in the flow of gene expression is one of the most fundamental goals in molecular biology. In this work, we have investigated several protein turnover-related steps in the context of gene expression regulation in response to changes in external temperature in model yeast Saccharomyces cerevisiae. We have found that the regulation of protein homeostasis is stricter than mRNA homeostasis. Although global translation and protein degradation rates are found to increase with temperature, the increase of the catalytic activity of ribosomes is higher than the global translation rate suggesting that yeast cells adapt the amount of translational machinery to…
Interaction between ROR1 and MuSK activation complex in myogenic cells
2017
The ROR family of receptor tyrosine kinases, ROR1 and ROR2, is known to play an important role during skeletal muscle regeneration. ROR1 has a critical role in regulating satellite cell (SC) proliferation during muscle regeneration, and proinflammatory cytokines such as TNF-α and IL-1β can induce expression of ROR1 in myogenic cells via NF-κB activation. While searching for ROR1-interacting proteins in myogenic cells, we identified MuSK as a ROR1-binding protein. MuSK interacts with and phosphorylates ROR1 at the cytoplasmic proline-rich domain. ROR1 also interacts with the MuSK activator Dok-7 independently of MuSK interaction. Collectively, our results identified ROR1 as a new interacting…
SNVSniffer: an integrated caller for germline and somatic single-nucleotide and indel mutations
2016
Various approaches to calling single-nucleotide variants (SNVs) or insertion-or-deletion (indel) mutations have been developed based on next-generation sequencing (NGS). However, most of them are dedicated to a particular type of mutation, e.g. germline SNVs in normal cells, somatic SNVs in cancer/tumor cells, or indels only. In the literature, efficient and integrated callers for both germline and somatic SNVs/indels have not yet been extensively investigated. We present SNVSniffer, an efficient and integrated caller identifying both germline and somatic SNVs/indels from NGS data. In this algorithm, we propose the use of Bayesian probabilistic models to identify SNVs and investigate a mult…
LEGO-based generalized set of two linear algebraic 3D bio-macro-molecular descriptors: Theory and validation by QSARs
2019
Abstract Novel 3D protein descriptors based on bilinear, quadratic and linear algebraic maps in R n are proposed. The latter employs the kth 2-tuple (dis) similarity matrix to codify information related to covalent and non-covalent interactions in these biopolymers. The calculation of the inter-amino acid distances is generalized by using several dis-similarity coefficients, where normalization procedures based on the simple stochastic and mutual probability schemes are applied. A new local-fragment approach based on amino acid-types and amino acid-groups is proposed to characterize regions of interest in proteins. Topological and geometric macromolecular cutoffs are defined using local and…
Thiazole–amino acids: influence of thiazole ring on conformational properties of amino acid residues
2021
Abstract Post-translational modified thiazole–amino acid (Xaa–Tzl) residues have been found in macrocyclic peptides (e.g., thiopeptides and cyanobactins), which mostly inhibit protein synthesis in Gram + bacteria. Conformational study of the series of model compounds containing this structural motif with alanine, dehydroalanine, dehydrobutyrine and dehydrophenylalanine were performed using DFT method in various environments. The solid-state crystal structure conformations of thiazole–amino acid residues retrieved from the Cambridge Structural Database were also analysed. The studied structural units tend to adopt the unique semi-extended β2 conformation; which is stabilised mainly by N–H⋯N…
The mRNA cap-binding protein Cbc1 is required for high and timely expression of genes by promoting the accumulation of gene-specific activators at pr…
2015
The highly conserved Saccharomyces cerevisiae cap-binding protein Cbc1/Sto1 binds mRNA co-transcriptionally and acts as a key coordinator of mRNA fate. Recently, Cbc1 has also been implicated in transcription elongation and pre-initiation complex (PIC) formation. Previously, we described Cbc1 to be required for cell growth under osmotic stress and to mediate osmostress-induced translation reprogramming. Here, we observe delayed global transcription kinetics in cbc1Δ during osmotic stress that correlates with delayed recruitment of TBP and RNA polymerase II to osmo-induced promoters. Interestingly, we detect an interaction between Cbc1 and the MAPK Hog1, which controls most gene expression c…