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81.
Lu Wang Weihua Hu Chengpeng Fan 《Protein science : a publication of the Protein Society》2020,29(5):1228-1241
Swine acute diarrhea syndrome coronavirus (SADS‐CoV) is a novel coronavirus that is involved in severe diarrhea disease in piglets, causing considerable agricultural and economic loss in China. The emergence of this new coronavirus increases the importance of understanding SADS‐CoV as well as antivirals. Coronaviral proteases, including main proteases and papain‐like proteases (PLP), are attractive antiviral targets because of their essential roles in polyprotein processing and thus viral maturation. Here, we describe the biochemical and structural identification of recombinant SADS papain‐like protease 2 (PLP2) domain of nsp3. The SADS‐CoV PLP2 was shown to cleave nsp1 proteins and also peptides mimicking the nsp2|nsp3 cleavage site and also had deubiquitinating and deISGynating activity by in vitro assays. The crystal structure adopts an architecture resembling that of PLPs from other coronaviruses. We characterize both conserved and unique structural features likely directing the interaction of PLP2 with the substrates, including the tentative mapping of active site and other essential residues. These results provide a foundation for understanding the molecular basis of coronaviral PLPs' catalytic mechanism and for the screening and design of therapeutics to combat infection by SADS coronavirus. 相似文献
82.
83.
Alejandro Ruete Debora Arlt ke Berg Jonas Knape Micha mihorski Tomas Prt 《Ecology and evolution》2020,10(18):10057-10065
Abundant citizen science data on species occurrences are becoming increasingly available and enable identifying composition of communities occurring at multiple sites with high temporal resolution. However, for species displaying temporary patterns of local occurrences that are transient to some sites, biodiversity measures are clearly dependent on the criteria used to include species into local species lists. Using abundant opportunistic citizen science data from frequently visited wetlands, we investigated the sensitivity of α‐ and β‐diversity estimates to the use raw versus detection‐corrected data and to the use of inclusion criteria for species presence reflecting alternative site use. We tested seven inclusion criteria (with varying number of days required to be present) on time series of daily occurrence status during a breeding season of 90 days for 77 wetland bird species. We show that even when opportunistic presence‐only observation data are abundant, raw data may not produce reliable local species richness estimates and rank sites very differently in terms of species richness. Furthermore, occupancy model based α‐ and β‐diversity estimates were sensitive to the inclusion criteria used. Total species lists (all species observed at least once during a season) may therefore mask diversity differences among sites in local communities of species, by including vagrant species on potentially breeding communities and change the relative rank order of sites in terms of species richness. Very high sampling effort does not necessarily free opportunistic data from its inherent bias and can produce a pattern in which many species are observed at least once almost everywhere, thus leading to a possible paradox: The large amount of biological information may hinder its usefulness. Therefore, when prioritizing among sites to manage or preserve species diversity estimates need to be carefully related to relevant inclusion criteria depending on the diversity estimate in focus. 相似文献
84.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):576-582
A novel method has been developed for the synthesis of α-oxycarbanilino phosphonates through a reaction of α-hydroxyphosphonates with isocyanate under microwave irradiation. The synthesized compounds were evaluated for their acetylcholinesterase (AChE) inhibition potency through IC50determination. Molecular modelling studies suggest that the most potent inhibitor (compound 4h, IC50 = 6.36 µM) is bound to the peripheral site of AChE, which suggests that it decreases the catalytic activity not through binding to the active site but through blocking the entrance of the active site gorge. This puts forward the potential of compound 4h and its derivatives to be used in the design of dual inhibitors: inhibition of the catalytic activity of AChE and of amyloid β aggregation. 相似文献
85.
Dispersal is a key process in population and evolutionary ecology. Individual decisions are affected by fitness consequences of dispersal, but these are difficult to measure in wild populations. A long‐term dataset on a geographically closed bird population, the Mauritius kestrel, offers a rare opportunity to explore fitness consequences. Females dispersed further when the availability of local breeding sites was limited, whereas male dispersal correlated with phenotypic traits. Female but not male fitness was lower when they dispersed longer distances compared to settling close to home. These results suggest a cost of dispersal in females. We found evidence of both short‐ and long‐term fitness consequences of natal dispersal in females, including reduced fecundity in early life and more rapid aging in later life. Taken together, our results indicate that dispersal in early life might shape life history strategies in wild populations. 相似文献
86.
Ten years of restoration work at 200 sites within Kosciuszko National Park – sites damaged during the construction of Australia's most iconic hydroelectric scheme – is showing substantial progress and is contributing to the protection of the park's internationally significant ecosystems. 相似文献
87.
Peter Hlavica 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(1):205-220
Fungi belong to the large kingdom of lower eukaryotic organisms encompassing yeasts along with filamentous and dimorphic members. Microbial P450 enzymes have contributed to exploration of and adaptation to diverse ecological niches such as conversion of lipophilic compounds to more hydrophilic derivatives or degradation of a vast array of environmental toxicants. To better understand diversification of the catalytic behavior of fungal P450s, detailed insight into the molecular machinery steering oxidative attack on the distinctly structured endogenous and xenobiotic substrates is of preeminent interest. Based on a general, CYP102A1-related template the bulk of predicted substrate/inhibitor-binding determinants were shown to cluster near the distal heme face within the six known substrate recognition sites (SRSs) made up by the α-helical B′/F/G/I tetrad, the B′–C interhelical loop and strands of the β6-sheet, population density being highest in the structurally flexible SRS-1 and SRS-4 domains, showing a low degree of conservation. Reactivity toward ligands favorably coincides with the lipophilicity/hydrophilicity profile and bulkiness of critical amino acids acting as selective filters. Some decisive elements may also serve in maintenance of catalytic competence via their action as gatekeepers directing substrate access/positioning or stabilizers of the heme environment enabling dioxygen activation. Non-SRS residues seem to control spin state equilibria and attract redox partners by electrostatic forces. Of note, the inhibitory potency of azole-type fungicides is likely to arise from perturbation of the complex interplay of the mechanistic principles addressed above. Knowledge-supported exploitation of the topological data will be helpful in the manufacture of commodity/specialty chemicals as well as therapeutic agents. Also, engineered fungal P450s may be used to improve pollutant-specific bioremediation of contaminated soils. 相似文献
88.
89.
Alzheimer's disease is one of the most common causes of dementia. It is believed that the aggregation of short Aβ -peptides to form oligomeric and protofibrillar amyloid assemblies plays a central role for disease-relevant neurotoxicity. In recent years, passive immunotherapy has been introduced as a potential treatment strategy with anti-amyloid antibodies binding to Aβ -amyloids and inducing their subsequent degradation by the immune system. Although so far mostly unsuccessful in clinical studies, the high-dosed application of the monoclonal antibody Aducanumab has shown therapeutic potential that might be attributed to its much greater affinity to Aβ -aggregates vs monomeric Aβ -peptides. In order to better understand how Aducanumab interacts with aggregated Aβ -forms compared to monomers, we have generated structural model complexes based on the known structure of Aducanumab in complex with an Aβ2 − 7 -eptitope. Structural models of Aducanumab bound to full-sequence Aβ1 − 40 -monomers, oligomers, protofilaments and mature fibrils were generated and investigated using extensive molecular dynamics simulations to characterize the flexibility and possible additional interactions. Indeed, an aggregate-specific N-terminal binding motif was found in case of Aducanumab binding to oligomers, protofilaments and fibrils that is located next to but not overlapping with the epitope binding site found in the crystal structure with Aβ2 − 7 . Analysis of binding energetics indicates that this motif binds weaker than the epitope but likely contributes to Aducanumab's preference for aggregated Aβ -species. The predicted aggregate-specific binding motif could potentially serve as a basis to reengineer Aducanumab for further enhanced preference to bind Aβ -aggregates vs monomers. 相似文献
90.