Recognition motif and mechanism of ripening inhibitory peptides in plant hormone receptor ETR1

Synthetic peptides derived from ethylene-insensitive protein 2 (EIN2), a central regulator of ethylene signalling, were recently shown to delay fruit ripening by interrupting protein–protein interactions in the ethylene signalling pathway. Here, we show that the inhibitory peptide NOP-1 binds to the GAF domain of ETR1 – the prototype of the plant ethylene receptor family. Site-directed mutagenesis and computational studies reveal the peptide interaction site and a plausible molecular mechanism for the ripening inhibition

Enzyme adaptation to habitat thermal legacy shapes the thermal plasticity of marine microbiomes

Microbial communities respond to temperature with physiological adaptation and compositional turnover. Whether thermal selection of enzymes explains marine microbiome plasticity in response to temperature remains unresolved. By quantifying the thermal behaviour of seven functionally-independent enzyme classes (esterase, extradiol dioxygenase, phosphatase, beta-galactosidase, nuclease, transaminase, and aldo-keto reductase) in native proteomes of marine sediment microbiomes from the Irish Sea to the southern Red Sea, we record a significant effect of the mean annual temperature (MAT) on enzyme response in all cases. Activity and stability profiles of 228 esterases and 5 extradiol dioxygenases from sediment and seawater across 70 locations worldwide validate this thermal pattern. Modelling the esterase phase transition temperature as a measure of structural flexibility confirms the observed relationship with MAT. Furthermore, when considering temperature variability in sites with non-significantly different MATs, the broadest range of enzyme thermal behaviour and the highest growth plasticity of the enriched heterotrophic bacteria occur in samples with the widest annual thermal variability. These results indicate that temperature-driven enzyme selection shapes microbiome thermal plasticity and that thermal variability finely tunes such processes and should be considered alongside MAT in forecasting microbial community thermal response

Alternative Functions of Core Cell Cycle Regulators in Neuronal Migration, Neuronal Maturation, and Synaptic Plasticity

Recent studies have demonstrated that boundaries separating a cycling cell from a postmitotic neuron are not as concrete as expected. Novel and unique physiological functions in neurons have been ascribed for proteins fundamentally required for cell cycle progression and control. These “core” cell cycle regulators serve diverse postmitotic functions that span various developmental stages of a neuron, including neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis, and synaptic maturation and plasticity. In this review, we detail the nonproliferative postmitotic roles that these cell cycle proteins have recently been reported to play, the significance of their expression in neurons, mechanistic insight when available, and future prospects.National Institutes of Health (U.S.) (PO1 grant AG27916)National Institutes of Health (U.S.) (RO1 grant NS51876

Synthetic biology to access and expand nature's chemical diversity

Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Accessing these natural products promises to reinvigorate drug discovery pipelines and provide novel routes to synthesize complex chemicals. The pathways leading to the production of these molecules often comprise dozens of genes spanning large areas of the genome and are controlled by complex regulatory networks with some of the most interesting molecules being produced by non-model organisms. In this Review, we discuss how advances in synthetic biology — including novel DNA construction technologies, the use of genetic parts for the precise control of expression and for synthetic regulatory circuits — and multiplexed genome engineering can be used to optimize the design and synthesis of pathways that produce natural products

Das Außen im Innen : oder die Frage ob es eine Freiheit des Denkens gibt

Christopher PflegerKlagenfurt, Alpen-Adria-Univ., Dipl.-Arb., 2014(VLID)241346

Converging a Knowledge-Based Scoring Function: DrugScore2018

We present DrugScore2018, a new version of the knowledge-based scoring functionDrugScore, which builds upon the same formalism used to derive DrugScore, but exploits atraining data set of nearly 40,000 X-ray complex structures, a highly diverse and the by farlargest dataset ever used for such an endeavour. About 2.5 times as many pair potentials thanbefore now have a data basis required to yield smooth potentials, and pair potentials could nowbe derived for eight more atom types, including interactions involving halogen atoms and metalions highly relevant for medicinal chemistry. Probing for dependence on training data set sizeand quality, we show that DrugScore2018 potentials are converged. We evaluated DrugScore2018in comprehensive scoring, ranking, docking, and screening tests on the CASF-2013 dataset,allowing for a comparison with >30 other scoring functions. There, DrugScore2018 showedsimilar or improved performance in all aspects when compared to either DrugScore,DrugScoreCSD, or DSX and was, overall, the scoring function showing a most consistently goodperformance in scoring, ranking, and docking tests. Applying DrugScore2018 as objectivefunction in AutoDock3 in a large-scale docking trial, using 4,056 protein-ligand complexesfrom PDBbind 2016, reproduced a docked pose to within 2 Å RMSD to the crystal structure in>75% of all dockings. These results are remarkable as the DrugScore2018 potentials werederived from crystallographic information only, without any further adaptation using bindingaffinity or docking decoy data. DrugScore2018 should thus be a competitive scoring andobjective function for structure-based ligand design purposes

Physiological, Biochemical, and Structural Bioinformatic Analysis of the Multiple Inositol Dehydrogenases from Corynebacterium glutamicum

Inositols (cyclohexanehexols) comprise nine isomeric cyclic sugar alcohols, several of which occur in all domains of life with various functions. Many bacteria can utilize inositols as carbon and energy sources via a specific pathway involving inositol dehydrogenases (IDHs) as the first step of catabolism. The microbial cell factory Corynebacterium glutamicum can grow with myo-inositol as a sole carbon source. Interestingly, this species encodes seven potential IDHs, raising the question of the reason for this multiplicity. We therefore investigated the seven IDHs to determine their function, activity, and selectivity toward the biologically most important isomers myo-, scyllo-, and d-chiro-inositol. We created an ΔIDH strain lacking all seven IDH genes, which could not grow on the three inositols. scyllo- and d-chiro-inositol were identified as novel growth substrates of C. glutamicum. Complementation experiments showed that only four of the seven IDHs (IolG, OxiB, OxiD, and OxiE) enabled growth of the ΔIDH strain on two of the three inositols. The kinetics of the four purified enzymes agreed with the complementation results. IolG and OxiD are NAD+-dependent IDHs accepting myo- and d-chiro-inositol but not scyllo-inositol. OxiB is an NAD+-dependent myo-IDH with a weak activity also for scyllo-inositol but not for d-chiro-inositol. OxiE on the other hand is an NAD+-dependent scyllo-IDH showing also good activity for myo-inositol and a very weak activity for d-chiro-inositol. Structural models, molecular docking experiments, and sequence alignments enabled the identification of the substrate binding sites of the active IDHs and of residues allowing predictions on the substrate specificity. IMPORTANCE myo-, scyllo-, and d-chiro-inositol are C6 cyclic sugar alcohols with various biological functions, which also serve as carbon sources for microbes. Inositol catabolism starts with an oxidation to keto-inositols catalyzed by inositol dehydrogenases (IDHs). The soil bacterium C. glutamicum encodes seven potential IDHs. Using a combination of microbiological, biochemical, and modeling approaches, we analyzed the function of these enzymes and identified four IDHs involved in the catabolism of inositols. They possess distinct substrate preferences for the three isomers, and modeling and sequence alignments allowed the identification of residues important for substrate specificity. Our results expand the knowledge of bacterial inositol metabolism and provide an important basis for the rational development of producer strains for these valuable inositols, which show pharmacological activities against, e.g., Alzheimer's disease, polycystic ovarian syndrome, or type II diabetes. Keywords: Corynebacterium glutamicum; d-chiro-inositol; enzyme kinetics; inositol dehydrogenase; inositol metabolism; inositols; molecular docking; myo-inositol; scyllo-inositol; structural models