Where are the new herbicides? Qu, Ren‐Yu; He, Bo; Yang, Jing‐Fang ...
Pest management science,
June 2021, 2021-Jun, 2021-06-00, 20210601, Letnik:
77, Številka:
6
Journal Article
Abstract
Protein dynamics is central to all biological processes, including signal transduction, cellular regulation and biological catalysis. Among them, in-depth exploration of ligand-driven ...protein dynamics contributes to an optimal understanding of protein function, which is particularly relevant to drug discovery. Hence, a wide range of computational tools have been designed to investigate the important dynamic information in proteins. However, performing and analyzing protein dynamics is still challenging due to the complicated operation steps, giving rise to great difficulty, especially for nonexperts. Moreover, there is a lack of web protocol to provide online facility to investigate and visualize ligand-driven protein dynamics. To this end, in this study, we integrated several bioinformatic tools to develop a protocol, named Ligand and Receptor Molecular Dynamics (LARMD, http://chemyang.ccnu.edu.cn/ccb/server/LARMD/ and http://agroda.gzu.edu.cn:9999/ccb/server/LARMD/), for profiling ligand-driven protein dynamics. To be specific, estrogen receptor (ER) was used as a case to reveal ERβ-selective mechanism, which plays a vital role in the treatment of inflammatory diseases and many types of cancers in clinical practice. Two different residues (Ile373/Met421 and Met336/Leu384) in the pocket of ERβ/ERα were the significant determinants for selectivity, especially Met336 of ERβ. The helix H8, helix H11 and H7-H8 loop influenced the migration of selective agonist (WAY-244). These computational results were consistent with the experimental results. Therefore, LARMD provides a user-friendly online protocol to study the dynamic property of protein and to design new ligand or site-directed mutagenesis.
Diaryl ether (DE) is a functional scaffold existing widely both in natural products (NPs) and synthetic organic compounds. Statistically, DE is the second most popular and enduring scaffold within ...the numerous medicinal chemistry and agrochemical reports. Given its unique physicochemical properties and potential biological activities, DE nucleus is recognized as a fundamental element of medicinal and agrochemical agents aimed at different biological targets. Its drug-like derivatives have been extensively synthesized with interesting biological features including anticancer, anti-inflammatory, antiviral, antibacterial, antimalarial, herbicidal, fungicidal, insecticidal, and so on. In this review, we highlight the medicinal and agrochemical versatility of the DE motif according to the published information in the past decade and comprehensively give a summary of the target recognition, structure–activity relationship (SAR), and mechanism of action of its analogues. It is expected that this profile may provide valuable guidance for the discovery of new active ingredients both in drug and pesticide research.
Slow‐binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off‐target rates is restricted by a limited ...understanding of the structural basis of slow‐binding inhibition kinetics in enzyme–drug interactions. 4‐Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time‐dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow‐binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C‐terminal α‐helix in the inhibitor‐bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time‐dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD‐targeted drugs or herbicides with longer target residence time and improved properties.
Database
Structure data are available in the PDB under the accession numbers 5CTO (released), 5DHW (released), and 5YWG (released).
4‐Hydroxyphenylpyruvate dioxygenase (HPPD) is a target for drug and herbicide development. Although the slow‐binding behavior of HPPD inhibitors has been studied for decades, its mechanism remains unclear. We combined the enzyme kinetics, crystallography and computational simulations study to explore the mechanism, and identified that the steric hindrance of Phe428 of Arabidopsis thaliana HPPD is highly associated with the slow‐binding behavior of HPPD inhibitors. These findings enable the rational design of novel HPPD‐targeted inhibitors with improved properties.
Summary
In eukaryotes, mechanisms such as alternative splicing (AS) and alternative translation initiation (ATI) contribute to organismal protein diversity. Specifically, splicing factors play ...crucial roles in responses to environment and development cues; however, the underlying mechanisms are not well investigated in plants. Here, we report the parallel employment of short‐read RNA sequencing, single molecule long‐read sequencing and proteomic identification to unravel AS isoforms and previously unannotated proteins in response to abscisic acid (ABA) treatment. Combining the data from the two sequencing methods, approximately 83.4% of intron‐containing genes were alternatively spliced. Two AS types, which are referred to as alternative first exon (AFE) and alternative last exon (ALE), were more abundant than intron retention (IR); however, by contrast to AS events detected under normal conditions, differentially expressed AS isoforms were more likely to be translated. ABA extensively affects the AS pattern, indicated by the increasing number of non‐conventional splicing sites. This work also identified thousands of unannotated peptides and proteins by ATI based on mass spectrometry and a virtual peptide library deduced from both strands of coding regions within the Arabidopsis genome. The results enhance our understanding of AS and alternative translation mechanisms under normal conditions, and in response to ABA treatment.
Significance Statement
In this study, a customized analytical pipeline was developed to study transcriptional and translational changes during the abscisic acid response in plants. Using single molecule long‐read sequencing and short‐read RNA sequencing, we identified numerous alternative spliced (AS) transcripts in Arabidopsis and characterized two new AS types. Proteomic identification indicates differentially expressed AS events were more likely to undergo protein translation. The entire workflow is applicable for other plant species.
The phytohormone abscisic acid (ABA) is the best‐known stress signaling molecule in plants. ABA protects sessile land plants from biotic and abiotic stresses. The conserved pyrabactin ...resistance/pyrabactin resistance‐like/regulatory component of ABA receptors (PYR/PYL/RCAR) perceives ABA and triggers a cascade of signaling events. A thorough knowledge of the sequential steps of ABA signaling will be necessary for the development of chemicals that control plant stress responses. The core components of the ABA signaling pathway have been identified with adequate characterization. The information available concerning ABA biosynthesis, transport, perception, and metabolism has enabled detailed functional studies on how the protective ability of ABA in plants might be modified to increase plant resistance to stress. Some of the significant contributions to chemical manipulation include ABA biosynthesis inhibitors, and ABA receptor agonists and antagonists. Chemical manipulation of key control points in ABA signaling is important for abiotic and biotic stress management in agriculture. However, a comprehensive review of the current knowledge of chemical manipulation of ABA signaling is lacking. Here, a thorough analysis of recent reports on small‐molecule modulation of ABA signaling is provided. The challenges and prospects in the chemical manipulation of ABA signaling for the development of ABA‐based agrochemicals are also discussed.
Small molecules that can manipulate abscisic acid (ABA) signaling events are designed, developed, and evaluated. The ABA‐mediated stress adaptive responses of plants are mimicked by small molecules, and the ABA biosynthesis and catabolism events are altered by inhibitors. This approach is a novel way to gain chemical control over plant stress by using safer ABA‐based agrochemicals.
SUMMARY
Intron‐containing genes have the ability to generate multiple transcript isoforms by splicing, thereby greatly expanding the eukaryotic transcriptome and proteome. In eukaryotic cells, ...precursor mRNA (pre‐mRNA) splicing is performed by a mega‐macromolecular complex defined as a spliceosome. Among its splicing components, U1 small nuclear ribonucleoprotein (U1 snRNP) is the smallest subcomplex involved in early spliceosome assembly and 5′‐splice site recognition. Its central component, named U1‐70K, has been extensively characterized in animals and yeast. Very few investigations on U1‐70K genes have been conducted in plants, however. To this end, we performed a comprehensive study to systematically identify 115 U1‐70K genes from 67 plant species, ranging from algae to angiosperms. Phylogenetic analysis suggested that the expansion of the plant U1‐70K gene family was likely to have been driven by whole‐genome duplications. Subsequent comparisons of gene structures, protein domains, promoter regions and conserved splicing patterns indicated that plant U1‐70Ks are likely to preserve their conserved molecular function across plant lineages and play an important functional role in response to environmental stresses. Furthermore, genetic analysis using T‐DNA insertion mutants suggested that Arabidopsis U1‐70K may be involved in response to osmotic stress. Our results provide a general overview of this gene family in Viridiplantae and will act as a reference source for future mechanistic studies on this U1 snRNP‐specific splicing factor.
Significance Statement
This study describes a comprehensive analysis to systematically name and identify 115 U1‐70K genes from 67 plant species, ranging from algae to angiosperms.
...it is important to shed light on the complex network of interactions that involves SRPs and their stress‐induced expression. ...this is complicated by the facts that some SRPs are still unknown, ...and available information is scattered in a large number of publications and various databases. ...it would be useful to collect all the available information about plant SRPs together with their stress‐related expression characteristics into a unique resource, which would facilitate the discovery of new stress‐tolerant genes. Notably, this database was designed to provide comprehensive information for plant SRPs and facilitate the comparison of different SRPs in response to stress conditions (Figure 1a). ...SRPs were organized into five categories, namely small nuclear ribonucleoproteins, splicing factors, splicing regulatory proteins, novel spliceosome proteins and possible splicing‐related proteins, which may help us sort out the genetics of each transcript isoform that is potentially functional under stress treatment. ...the analysis of the expression of SRPs in shoot and root tissues under 9 abiotic stress treatments, namely cold, osmosis, salt, drought, genotoxicity, oxidation, UV‐B, wounding and heat, was performed. 1 Figure.
Abstract
Drug resistance is one of the most intractable issues for successful treatment in current clinical practice. Although many mutations contributing to drug resistance have been identified, the ...relationship between the mutations and the related pharmacological profile of drug candidates has yet to be fully elucidated, which is valuable both for the molecular dissection of drug resistance mechanisms and for suggestion of promising treatment strategies to counter resistant. Hence, effective prediction approach for estimating the sensitivity of mutations to agents is a new opportunity that counters drug resistance and creates a high interest in pharmaceutical research. However, this task is always hampered by limited known resistance training samples and accurately estimation of binding affinity. Upon this challenge, we successfully developed Auto In Silico Macromolecular Mutation Scanning (AIMMS), a web server for computer-aided de novo drug resistance prediction for any ligand–protein systems. AIMMS can qualitatively estimate the free energy consequences of any mutations through a fast mutagenesis scanning calculation based on a single molecular dynamics trajectory, which is differentiated with other web services by a statistical learning system. AIMMS suite is available at http://chemyang.ccnu.edu.cn/ccb/server/AIMMS/.
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