31 research outputs found
Novel Allosteric Sites on Ras for Lead Generation
Aberrant Ras activity is a hallmark of diverse cancers and developmental diseases. Unfortunately, conventional efforts to develop effective small molecule Ras inhibitors have met with limited success. We have developed a novel multi-level computational approach to discover potential inhibitors of previously uncharacterized allosteric sites. Our approach couples bioinformatics analysis, advanced molecular simulations, ensemble docking and initial experimental testing of potential inhibitors. Molecular dynamics simulation highlighted conserved allosteric coupling of the nucleotide-binding switch region with distal regions, including loop 7 and helix 5. Bioinformatics methods identified novel transient small molecule binding pockets close to these regions and in the vicinity of the conformationally responsive switch region. Candidate binders for these pockets were selected through ensemble docking of ZINC and NCI compound libraries. Finally, cell-based assays confirmed our hypothesis that the chosen binders can inhibit the downstream signaling activity of Ras. We thus propose that the predicted allosteric sites are viable targets for the development and optimization of new drugs
Climate change jeopardizes the persistence of freshwater zooplankton by reducing both habitat suitability and demographic resilience
Recommended from our members
Germination timing and chilling exposure create contingency in life history and influence fitness in the native wildflower Streptanthus tortuosus
The timing of life history events, such as germination and reproduction, influences ecological and selective environments throughout the life cycle. Many organisms evolve responses to seasonal environmental cues to synchronize these key events with favourable conditions. Often the fitness consequences of each life history transition depend on previous and subsequent events in the life cycle. If so, shifts in environmental cues can create cascading effects throughout the life cycle, which can influence fitness, selection on life history traits, and population viability. We examined variation in cue responses for contingent life history expression and fitness in a California native wildflower, Streptanthus tortuosus, by manipulating seasonal germination timing in a common garden experiment. We also manipulated chilling exposure to test the role of vernalization cues for seasonal life history contingency. Plants germinating early in the growing season in autumn were more likely to flower in the first year and less likely to perennate than later germinants in spring. First-year reproduction and overall fitness was the highest for autumn cohorts. Sensitivity analyses showed that optimal germination date depended on survival beyond the first year and fruit production in later years. Experimental chilling exposure induced first-year flowering in spring germinants, demonstrating that seasonal life history contingency is mediated by a vernalization requirement. This requirement reduced fitness of spring germinants without increasing survival or later fecundity and may be maladaptive. Such mismatches between cues and fitness may become more pervasive as predicted climate change reduces exposure to chilling, shortens growing seasons, and increases severity of summer drought. Synthesis. Shifts in germination timing in seasonal environments can cause cascading effects on trait expression and fitness that extend beyond the first year of the life cycle. Climate change is likely to shift seasonal conditions, influencing such life history contingency, with significant impacts on trait expression, fitness, and population persistence. These shifts may cause strong natural selection on cue sensitivity and life history expression, but it is an open question whether populations have the potential for rapid adaptation in response to this selection
Germination heterochrony in annual plants of Salsola L.: an effective survival strategy in changing environments
Critical nucleus of Greek-key-like core of α-synuclein protofibril and its disruption by dopamine and norepinephrine
Established and proposed roles of xanthine oxidoreductase in oxidative and reductive pathways in plants
Xanthine oxidoreductase (XOR) is among the most-intensively studied enzymes known to participate in the consumption of oxygen in cells. However, it attracted the attention of researchers due its participation in free radical production in vivo, mainly through the production of superoxide radicals. In plants, XOR is a key enzyme in purine degradation where it catalyzes the oxidation of hypoxanthine to xanthine and of xanthine to uric acid. Both reactions are accompanied by electron transfer to either NAD+ with simultaneous formation of NADH or to molecular oxygen, which results in formation of superoxides. Characterization of plant XOR mutants and isolated XOR proteins from various plant species provided evidence that the enzyme plays significant roles in plant growth, leaf senescence, fruit size, synthesis of nitrogen storage compounds, and plant-pathogen interactions. Moreover, the ability of XOR to carry out redox reactions as NADH oxidase and to produce reactive oxygen species and nitric oxide, together with a possible complementary role in abscisic acid synthesis have raised further attention on the importance of this enzyme. Based on these established and proposed functions, XOR is discussed as regulator of different processes of interest in plant biology and agriculture.The authors acknowledge the support of the research grants AGL2010-16167 to J.F.M. from the Spanish Ministry of Science and Innovation and Bi 1075/5-1 to F.B. by the Deutsche Forschungsgemeinschaft. R.E. received a JAE-Doctor grant from the Spanish Research Council (CSIC).