Common Structural Features Research Articles

Inhibition of chitin deacetylases to attenuate plant fungal diseases

Phytopathogenic fungi secrete chitin deacetylase (CDA) to escape the host’s immunological defense during infection. Here, we showed that the deacetylation activity of CDA toward chitin is essential for fungal virulence. Five crystal structures of two representative and phylogenetically distant phytopathogenic fungal CDAs, VdPDA1 from Verticillium dahliae and Pst_13661 from Puccinia striiformis f. sp. tritici, were obtained in ligand-free and inhibitor-bound forms. These structures suggested that both CDAs have an identical substrate-binding pocket and an Asp-His-His triad for coordinating a transition metal ion. Based on the structural identities, four compounds with a benzohydroxamic acid (BHA) moiety were obtained as phytopathogenic fungal CDA inhibitors. BHA exhibited high effectiveness in attenuating fungal diseases in wheat, soybean, and cotton. Our findings revealed that phytopathogenic fungal CDAs share common structural features, and provided BHA as a lead compound for the design of CDA inhibitors aimed at attenuating crop fungal diseases.

BRCT Domains: Structure, Functions, and Implications in Disease-New Therapeutic Targets for Innovative Drug Discovery against Infections.

The search for new therapeutic targets and their implications in drug development remains an emerging scientific topic. BRCT-bearing proteins are found in Archaea, Bacteria, Eukarya, and viruses. They are traditionally involved in DNA repair, recombination, and cell cycle control. To carry out these functions, BRCT domains are able to interact with DNA and proteins. Moreover, such domains are also implicated in several pathogenic processes and malignancies including breast, ovarian, and lung cancer. Although these domains exhibit moderately conserved folding, their sequences show very low conservation. Interestingly, sequence variations among species are considered positive traits in the search for suitable therapeutic targets, since non-specific drug interactions might be reduced. These main characteristics of BRCT, as well as its critical implications in key biological processes in the cell, have prompted the study of these domains as therapeutic targets. This review explores the possible roles of BRCT domains as therapeutic targets for drug discovery. We describe their common structural features and relevant interactions and pathways, as well as their implications in pathologic processes. Drugs commonly used to target these domains are also presented. Finally, based on their structures, we describe new drug design possibilities using modern and innovative techniques.

Mechanism of agonist-induced activation of the human itch receptor MRGPRX1.

Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are 4 primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 Å via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over other MRGPRXs and opioid receptor. MRGPRX1 was revealed to share common structural features of the Gq-mediated receptor activation mechanism of MRGPRX family members, but the variable residues in orthosteric pocket of MRGPRX1 exhibit the unique agonist recognition pattern, potentially facilitating to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.

A Bayesian hierarchical sparse factor model for estimating simultaneous covariance matrices for gestational outcomes in consecutive pregnancies.

Covariance estimation for multiple groups is a key feature for drawing inference from a heterogeneous population. One should seek to share information about common features in the dependence structures across the various groups. In this paper, we introduce a novel approach for estimating the covariance matrices for multiple groups using a hierarchical latent factor model that shrinks the factor loadings across groups toward a global value. Using a sparse spike and slab model on these loading coefficients allows for a sparse formulation of our model. Parameter estimation is accomplished through a Markov chain Monte Carlo scheme, and a model selection approach is used to select the number of factors to use. We validate our model through extensive simulation studies. Finally, we apply our methodology to the NICHD Consecutive Pregnancies Study to estimate the correlations between birth weights and gestational ages of three consecutive birth within four different subgroups (underweight, normal, overweight, and obese) of women.

Characterization and differentiation of sublittoral sandbanks in the southeastern North Sea

Marine sublittoral sandbanks are essential offshore feeding grounds for larger crustaceans, fish and seabirds. In the southern North Sea, sandbanks are characterized by considerable natural sediment dynamics and are subject to chronic bottom trawling. However, except for the Dogger Bank, sandbanks in the southeastern North Sea have been only poorly investigated until now. We used an extensive, multi-annual dataset covering ongoing national monitoring programmes, environmental impact assessments, and basic research studies to analyse benthic communities on sublittoral sandbanks, evaluating their ecological value against the backdrop of similar seafloor habitats in this region. The analysis revealed complex spatial structuring of sandy seafloor habitats of the southeastern North Sea. Different infauna clusters were identified and could be specified by their composition of characteristic species. The sandbanks shared common structural features in their infauna community composition although they were not necessarily characterized by particularly high biodiversity compared to other sandy habitats. A close association of one of the main bioturbators in the southern North Sea, the sea urchin Echinocardium cordatum, with sandbanks was detected, which may promote the sediment-bound biogeochemical activity in this particular seafloor habitat. This would corroborate the status of sandbanks as sites of high ecological value calling for consideration in marine conservation.

Gold–Sulfide Mineralization in the Manitanyrd Region, Polar Urals, Russia

This article describes the characteristics of gold–sulfide–quartz and gold–sulfide (gold–arsenic) ore occurrences in the Manitanyrd region of the Polar Urals. Ore occurrences are confined to NE-trending shear zones and have the common features of a geological structure. The host rocks are metamorphosed volcanic and volcanic–sedimentary rocks. We analyzed the mineral and chemical composition of the ore mineralization in all studied ore occurrences, showing that they belong to the same mineral type—pyrite–arsenopyrite, with a variable ratio of the main minerals. Arsenic pyrite is present in all ore occurrences. Two stages of ore formation were distinguished: early gold–pyrite–arsenopyrite with finely dispersed gold and late gold–galena–chalcopyrite–sphalerite with coarse gold, fahlore, and sulfosalts Pb, Cu, Bi, Sb. Native gold of the first generation, finely dispersed in arsenopyrite and pyrite, had an average to high fineness (800‰–1000‰) with a relatively low dispersion. Native gold of the second generation was larger, and its fineness in ore occurrences varied; in one of them, it varied from 300‰ to 950‰, while in others, it varied from 800‰ to 950‰. The isotope composition of sulfur in sulfides (δ34S) ranged between −0.2‰ and −8.0‰. δ34S values of sulfides in the range of −0.2‰ to −3.5‰ were similar to meteorite, indicating the participation of a single deep magmatic source of sulfur in the ore formation. According to the study of fluid inclusions, the formation of ore quartz veins occurs in the temperature range of 467–109 °C. The similarity of the geological–structural, mineralogical–geochemical, and isotope–geochemical features of the gold–sulfide–quartz and gold–sulfide occurrences in the area suggest their formation in a single hydrothermal system.

Crystal Structure of New 1-Phenyl-Substituted Tribenzsilatranes

The family of practically requested “common” silatrane derivatives of triethanolamine X-Si(OCH2CH2)3N, 1, was enlarged with the first representatives of 3,4,6,7,10,11-tribenzo-2,8,9trioxa-5-aza-1-silatricyclo(3.3.3.0^1,5^)undecanes X-Si(O-para-R-C6H3)3N, tribenzsilatranes 2 (R = H (a), Me (b), F (c)), carrying the substituent R in the side aromatic rings. These compounds were prepared via the transesterification of phenyl trimethoxysilane with the corresponding triphenol amines and studied using XRD and DFT calculations. These derivatives of 1-X-(4-R-2,2′,2′′-nitrilotriphenoxy)silane are expected to have, as their parent “common” silatranes 1, diverse biological and pharma activities. A common characteristic feature of the molecular structures of both 1 and 2 is the presence of an intramolecular dative bond N→Si whose existence is evidenced by geometric and quantum topological (AIM) criteria. In the crystals, the length of this bond (dSiN) is noticeably longer in tribenzsilatranes than in 1. The results of DFT B3PW91/6-311++G(d,p) calculations suggest the reason for this to be the more rigid nature of the potential functions of the N→Si bond deformation in 2 compared to 1. The relative degree of “softness”/”hardness” of the potential functions can be assessed from the difference in the calculated values of dSiN in isolated molecules 1 and 2a–c and in their crystals.

Discriminating Aromatic Parent Compounds and Their Derivative Isomers in Ice Grains From Enceladus and Europa Using a Laboratory Analogue for Spaceborne Mass Spectrometers

AbstractResults from the Cassini‐Huygens space mission at Enceladus revealed a substantial inventory of organic species embedded in plume and E ring ice grains originating from a global subsurface and putative habitable ocean. Compositional analysis by the Cosmic Dust Analyzer indicated the presence of aromatic species and constrained some structural features, although their exact nature remains unclear. As indicated by many studies, among other organic species, low‐mass aromatics likely played a role in the emergence of life on Earth and may be linked to potential prebiotic or biogenic chemistry on icy moons. Here, we study the behavior of single‐ringed aromatic compounds—benzoic acid and two isomeric derivatives, 2,3‐dihydroxybenzoic acid and 2,5‐dihydroxybenzoic acid—using Laser‐Induced Liquid Beam Ion Desorption (LILBID), an analogue setup to simulate the impact ionization mass spectra of ice grains in space. These compounds share common structural features but also exhibit differences in functional groups and substituent positions. We investigate the fragmentation behavior and spectral appearance of each molecule over three simulated impact velocities, in both positive and negative ion modes. Parent compounds can be distinguished easily from their derivatives due to various spectral differences, including the (de)protonated molecular ion peaks appearing at different m/z values. We conclude that distinction between structural isomers in LILBID is more challenging, but some insights can be revealed by considering intermolecular bonding regimes. This work will guide future investigations into elucidating the composition of isomeric biosignatures in ice grains, relevant for future space missions to Enceladus and Europa.

Epoxide-Based Synthetic Approaches toward Polypropionates and Related Bioactive Natural Products.

Polypropionate units are a common structural feature of many of the natural products in polyketides, some of which have shown a broad range of antimicrobial and therapeutic potential. Polypropionates are composed of a carbon skeleton with alternating methyl and hydroxy groups with a specific configuration. Different approaches have been developed for the synthesis of polypropionates and herein we include, for the first time, all of the epoxide-based methodologies that have been reported over the years by several research groups such as Kishi, Katsuki, Marashall, Miyashita, Prieto, Sarabia, Jung, McDonald, etc. Several syntheses of polypropionate fragments and natural products that employed epoxides as key intermediates have been described and summarized in this review. These synthetic approaches involve enatio- and diastereoselective synthesis of epoxides (epoxy-alcohols, epoxy-amides, and epoxy-esters) and their regioselective cleavage with carbon and/or hydride nucleophiles. In addition, we included a description of the isolation and biological activities of the polypropionates and related natural products that have been synthetized using epoxide-based approaches. In conclusion, the epoxide-based methodologies are a non-aldol alternative approach for the construction of polypropionate.

Phylogenetic analyses of 5-hydroxytryptamine 3 (5-HT3) receptors in Metazoa.

The 5-hydroxytrptamine 3 (5-HT3) receptor is a member of the 'Cys-loop' family and the only pentameric ligand gated ion channel among the serotonin receptors. 5-HT3 receptors play an important role in controlling growth, development, and behaviour in animals. Several 5-HT3 receptor antagonists are used to treat diseases (e.g., irritable bowel syndrome, nausea and emesis). Humans express five different subunits (A-E) enabling a variety of heteromeric receptors to form but all contain 5HT3A subunits. However, the information available about the 5-HT3 receptor subunit occurrence among the metazoan lineages is minimal. In the present article we searched for 5-HT3 receptor subunit homologs from different phyla in Metazoa. We identified more than 1000 5-HT3 receptor subunits in Metazoa in different phyla and undertook simultaneous phylogenetic analysis of 526 5HT3A, 358 5HT3B, 239 5HT3C, 70 5HT3D, and 173 5HT3E sequences. 5-HT3 receptor subunits were present in species belonging to 11 phyla: Annelida, Arthropoda, Chordata, Cnidaria, Echinodermata, Mollusca, Nematoda, Orthonectida, Platyhelminthes, Rotifera and Tardigrada. All subunits were most often identified in Chordata phylum which was strongly represented in searches. Using multiple sequence alignment, we investigated variations in the ligand binding region of the 5HT3A subunit protein sequences in the metazoan lineage. Several critical amino acid residues important for ligand binding (common structural features) are commonly present in species from Nematoda and Platyhelminth gut parasites through to Chordata. Collectively, this better understanding of the 5-HT3 receptor evolutionary patterns raises possibilities of future pharmacological challenges facing Metazoa including effects on parasitic and other species in ecosystems that contain 5-HT3 receptor ligands.

Alzheimer's Disease: Treatment of Multi-Factorial Disorders with Multi- Target Approach.

Alzheimer's Disease (AD) is a common neurodegenerative disorder that is almost incurable with the existing therapeutic interventions. Due to the high-risk factors associated with this disease, there is a global pursuit of new anti-AD agents. Herein, we explore the biochemical pathways which are responsible for the initiation/propagation of the disease. It is observed that out of the two isoforms of β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and β-site amyloid precursor protein cleaving enzyme 2 (BACE2) present in the brain, BACE1 plays the predominant role in the commencement of AD. Moreover, the catalytic activities of acetylcholinesterase and butyrylcholinesterase regulate the concentration of neurotransmitters, and they are needed to be kept under control during the signs of AD. Hence, these two enzymes also serve as potential targets for the treatment of AD patients. Keeping in view the multifactorial nature of the disease, we also reviewed the multitarget approach for the treatment of AD. It is tried to identify the common structural features of those molecules which act on different cellular targets during AD therapy.

Observation of a Plastic Crystal in Water-Ammonia Mixtures under High Pressure and Temperature.

Solid mixtures of ammonia and water, the so-called ammonia hydrates, are thought to be major components of solar and extra-solar icy planets. We present here a thorough characterization of the recently reported high pressure (P)-temperature (T) phase VII of ammonia monohydrate (AMH) using Raman spectroscopy, X-ray diffraction, and quasi-elastic neutron scattering (QENS) experiments in the ranges 4-10 GPa, 450-600 K. Our results show that AMH-VII exhibits common structural features with the disordered ionico-molecular alloy (DIMA) phase, stable above 7.5 GPa at 300 K: both present a substitutional disorder of water and ammonia over the sites of a body-centered cubic lattice and are partially ionic. The two phases however markedly differ in their hydrogen dynamics, and QENS measurements show that AMH-VII is characterized by free molecular rotations around the lattice positions which are quenched in the DIMA phase. AMH-VII is thus a peculiar crystalline solid in that it combines three types of disorder: substitutional, compositional, and rotational.

Arabinogalactan Structures of Repetitive Serine-Hydroxyproline Glycomodule Expressed by Arabidopsis Cell Suspension Cultures.

Arabinogalactan-proteins (AGPs) are members of the hydroxyproline-rich glycoprotein (HRGP) superfamily. They are heavily glycosylated with arabinogalactans, which are usually composed of a β-1,3-linked galactan backbone with 6-O-linked galactosyl, oligo-1,6-galactosyl, or 1,6-galactan side chains that are further decorated with arabinosyl, glucuronosyl, rhamnosyl, and/or fucosyl residues. Here, our work with Hyp-O-polysaccharides isolated from (Ser-Hyp)32-EGFP (enhanced green fluorescent protein) fusion glycoproteins overexpressed in transgenic Arabidopsis suspension culture is consistent with the common structural features of AGPs isolated from tobacco. In addition, this work confirms the presence of β-1,6-linkage on the galactan backbone identified previously in AGP fusion glycoproteins expressed in tobacco suspension culture. Furthermore, the AGPs expressed in Arabidopsis suspension culture lack terminal-rhamnosyl residues and have a much lower level of glucuronosylation compared with those expressed in tobacco suspension culture. These differences not only suggest the presence of distinct glycosyl transferases for AGP glycosylation in the two systems, but also indicate the existence of minimum AG structures for type II AG functional features.

Infrared and Visible Image Fusion via Attention-Based Adaptive Feature Fusion.

Infrared and visible image fusion methods based on feature decomposition are able to generate good fused images. However, most of them employ manually designed simple feature fusion strategies in the reconstruction stage, such as addition or concatenation fusion strategies. These strategies do not pay attention to the relative importance between different features and thus may suffer from issues such as low-contrast, blurring results or information loss. To address this problem, we designed an adaptive fusion network to synthesize decoupled common structural features and distinct modal features under an attention-based adaptive fusion (AAF) strategy. The AAF module adaptively computes different weights assigned to different features according to their relative importance. Moreover, the structural features from different sources are also synthesized under the AAF strategy before reconstruction, to provide a more entire structure information. More important features are thus paid more attention to automatically and advantageous information contained in these features manifests itself more reasonably in the final fused images. Experiments on several datasets demonstrated an obvious improvement of image fusion quality using our method.

Multi-component immune knockout: A strategy for studying the effective components of traditional Chinese medicine

Periploca forrestii Schltr., a traditional Chinese medicine (TCM), is commonly used to treat autoimmune diseases such as rheumatoid arthritis (RA). However, its mechanism, involving a variety of cardiac glycosides, remains largely unknown. The immune knockout strategy can highly selectively deplete target components by immunoaffinity chromatography (IAC). We aimed to identify the common structural features of cardiac glycosides in P. forrestii and design IAC to specifically recognize these features to achieve the multi-component knockout of potential active substances from the extracts of P. forrestii. A content detection experiment confirmed that the content of a compound with periplogenin structure (CPS) in the extract of P. forrestii was reduced by 45% by IAC of periplogenin. The immunosuppressive ability of the extract on H9 human T lymphocytic cells was weakened after CPS knockout from P. forrestii extract. Molecular biology experiments showed that mRNA expression of interferon-γ (IFN-γ), interleukin-2 (IL-2), and interleukin-6 (IL-6) in H9 cells was up-regulated after CPS knockout, while no significant changes in the expression of interleukin-4 (IL-4) were found. CPS knockout from P. forrestii extract did not cause significant changes in the proliferation of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells incubated with this extract. These results indicate that CPS exhibited immunosuppressive effects via inhibiting the T helper 1 (Th1) cell immune response and not via the anti-inflammatory components in P. forrestii. This is the first use of IAC to achieve multi-component knockout in TCM extracts for identifying effective compounds. This method is effective and reliable and warrants further exploration.

Four Routes to 3-(3-Methoxy-1,3-dioxopropyl)pyrrole, a Core Motif of Rings C and E in Photosynthetic Tetrapyrroles.

The photosynthetic tetrapyrroles share a common structural feature comprised of a β-ketoester motif embedded in an exocyclic ring (ring E). As part of a total synthesis program aimed at preparing native structures and analogues, 3-(3-methoxy-1,3-dioxopropyl)pyrrole was sought. The pyrrole is a precursor to analogues of ring C and the external framework of ring E. Four routes were developed. Routes 1-3 entail a Pd-mediated coupling process of a 3-iodopyrrole with potassium methyl malonate, whereas route 4 relies on electrophilic substitution of TIPS-pyrrole with methyl malonyl chloride. Together, the four routes afford considerable latitude. A long-term objective is to gain the capacity to create chlorophylls and bacteriochlorophylls and analogues thereof by facile de novo means for diverse studies across the photosynthetic sciences.

Catalytic Access to Chiral δ-Lactams via Nucleophilic Dearomatization of Pyridine Derivatives.

Nitrogen-bearing rings are common features in the molecular structures of modern drugs, with chiral δ-lactams being an important subclass due to their known pharmacological properties. Catalytic dearomatization of preactivated pyridinium ion derivatives emerged as a powerful method for the rapid construction of chiral N-heterocycles. However, direct catalytic dearomatization of simple pyridine derivatives are scarce and methodologies yielding chiral δ-lactams are yet to be developed. Herein, we describe an enantioselective C4-dearomatization of methoxypyridine derivatives for the preparation of functionalised enantioenriched δ-lactams using chiral copper catalysis. Experimental 13 C kinetic isotope effects and density functional theory calculations shed light on the reaction mechanism and the origin of enantioselectivity.

Catalytic Access to Chiral δ‐Lactams via Nucleophilic Dearomatization of Pyridine Derivatives

AbstractNitrogen‐bearing rings are common features in the molecular structures of modern drugs, with chiral δ‐lactams being an important subclass due to their known pharmacological properties. Catalytic dearomatization of preactivated pyridinium ion derivatives emerged as a powerful method for the rapid construction of chiral N‐heterocycles. However, direct catalytic dearomatization of simple pyridine derivatives are scarce and methodologies yielding chiral δ‐lactams are yet to be developed. Herein, we describe an enantioselective C4‐dearomatization of methoxypyridine derivatives for the preparation of functionalised enantioenriched δ‐lactams using chiral copper catalysis. Experimental 13C kinetic isotope effects and density functional theory calculations shed light on the reaction mechanism and the origin of enantioselectivity.

Identification and characterization of RNA pentaloop sequence families.

One of the current methods for predicting RNA tertiary structure is fragment-based homology, which predicts tertiary structure from secondary structure. For a successful prediction, this method requires a library of the tertiary structures of small motifs clipped from previously solved RNA 3D structures. Because of the limited number of available tertiary structures, it is not practical to find structures for all sequences of all motifs. Identifying sequence families for motifs can fill the gaps because all sequences within a family are expected to have similar structural features. Currently, a collection of well-characterized sequence families has been identified for tetraloops. Because of their prevalence and biological functions, pentaloop structures should also be well-characterized. In this study, 10 pentaloop sequence families are identified. For each family, the common and distinguishing structural features are highlighted. These sequence families can be used to predict the tertiary structure of pentaloop sequences for which a solved structure is not available.

Ligand and structure-based approaches for the exploration of structure-activity relationships of fusidic acid derivatives as antibacterial agents.

Introduction: Fusidic acid (FA) has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects. Purpose: Therefore, it is necessary to explore the structure-activity relationships of FA derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum. Methods and result: First, a pharmacophore model was established on the nineteen FA derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the FA derivatives were determined as those of six hydrophobic centers, two atom centers of the hydrogen bond acceptor, and a negative electron center around the C-21 field. Then, seven FA derivatives have been designed according to the reported structure-activity relationships and the pharmacophore characteristics. The designed FA derivatives were mapped on the pharmacophore model, and the Qfit values of all FA derivatives were over 50 and FA-8 possessed the highest value of 82.66. The molecular docking studies of the partial target compounds were conducted with the elongation factor G (EF-G) of S. aureus. Furthermore, the designed FA derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative FA-7 with a chlorine group as the substituent group at C-25 of FA displayed the best antibacterial property with an MIC of 3.125µM. Subsequently, 3D-QSAR was carried on all the derivatives by using the CoMSIA mode of SYBYL-X 2.0. Conclusion: Hence, a computer-aided drug design model was developed for FA, which can be further used to optimize FA derivatives as highly potent antibacterial agents.