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1.
Mathivanan Chinnaraj Robert Flaumenhaft Nicola Pozzi 《The Journal of biological chemistry》2022,298(8)
Human protein disulfide isomerase (PDI) is an essential redox-regulated enzyme required for oxidative protein folding. It comprises four thioredoxin domains, two catalytically active (a, a’) and two inactive (b, b’), organized to form a flexible abb’a’ U-shape. Snapshots of unbound oxidized and reduced PDI have been obtained by X-ray crystallography. Yet, how PDI’s structure changes in response to the redox environment and inhibitor binding remains controversial. Here, we used multiparameter confocal single-molecule FRET to track the movements of the two catalytic domains with high temporal resolution. We found that at equilibrium, PDI visits three structurally distinct conformational ensembles, two “open” (O1 and O2) and one “closed” (C). We show that the redox environment dictates the time spent in each ensemble and the rate at which they exchange. While oxidized PDI samples O1, O2, and C more evenly and in a slower fashion, reduced PDI predominantly populates O1 and O2 and exchanges between them more rapidly, on the submillisecond timescale. These findings were not expected based on crystallographic data. Using mutational analyses, we further demonstrate that the R300-W396 cation-π interaction and active site cysteines dictate, in unexpected ways, how the catalytic domains relocate. Finally, we show that irreversible inhibitors targeting the active sites of reduced PDI did not abolish these protein dynamics but rather shifted the equilibrium toward the closed ensemble. This work introduces a new structural framework that challenges current views of PDI dynamics, helps rationalize its multifaceted role in biology, and should be considered when designing PDI-targeted therapeutics. 相似文献
2.
Arrestin‐Domain Containing Protein 1 (Arrdc1) Regulates the Protein Cargo and Release of Extracellular Vesicles
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Sushma Anand Natalie Foot Ching‐Seng Ang Kelly M. Gembus Shivakumar Keerthikumar Christopher G. Adda Suresh Mathivanan Sharad Kumar 《Proteomics》2018,18(17)
Extracellular vesicles (EVs) are lipid‐bilayered vesicles that are released by multiple cell types and contain nucleic acids and proteins. Very little is known about how the cargo is packaged into EVs. Ubiquitination of proteins is a key posttranslational modification that regulates protein stability and trafficking to subcellular compartments including EVs. Recently, arrestin‐domain containing protein 1 (Arrdc1), an adaptor for the Nedd4 family of ubiquitin ligases, has been implicated in the release of ectosomes, a subtype of EV that buds from the plasma membrane. However, it is currently unknown whether Arrdc1 can regulate the release of exosomes, a class of EVs that are derived endocytically. Furthermore, it is unclear whether Arrdc1 can regulate the sorting of protein cargo into the EVs. Exosomes and ectosomes are isolated from mouse embryonic fibroblasts isolated from wild type and Arrdc1‐deficient (Arrdc1?/?) mice. Nanoparticle tracking analysis–based EV quantitation shows that Arrdc1 regulates the release of both exosomes and ectosomes. Proteomic analysis highlights the change in protein cargo in EVs upon deletion of Arrdc1. Functional enrichment analysis reveals the enrichment of mitochondrial proteins in ectosomes, while proteins implicated in apoptotic cleavage of cell adhesion proteins and formation of cornified envelope are significantly depleted in exosomes upon knockout of Arrdc1. 相似文献
3.
Abstract Leaf blight caused by Alternaria helianthi (Hansf.) Tubaki & Nishihara, is the major disease of sunflower affecting the successful cultivation across India. Five individual fungicides and two combination fungicides were evaluated against this pathogen in laboratory and in field experiments. Among them, the combination of carbendazim + mancozeb completely (100%) inhibited the mycelial growth of A. helianthi, irrespective of the concentrations tested followed by carbendazim alone and metalaxyl + mancozeb under in vitro condition. In field conditions, the combination of carbendazim + mancozeb was found to be highly effective in reducing the leaf blight disease of sunflower in all the three experiments as compared to other fungicides and unsprayed control. The reduction of Alternaria leaf blight was also directly associated with an increase in seed yield. The economics of the fungicides spray has been worked out and the benefit cost ratio for the combination of carbendazim + mancozeb at 2.0 g/l was 7.1 as compared to unsprayed control. The overall analysis of the results revealed that the combination of carbendazim + mancozeb at 2.0 g/l can be used for the management of foliar diseases such as Alternaria leaf spot/blight in agricultural crops. 相似文献
4.
Efrem Kentiba Soumitra Mondal D. Mathivanan Mala George 《Chronobiology international》2013,30(12):1742-1747
ABSTRACTThe purpose of this study was to compare chronotype preferences of college students from high- and low-altitude backgrounds living in a tropical setting of Ethiopia. Chronotype (morningness–eveningness) is a preference for a given time of day for physical or mental activities. The present cross-sectional study employed Horne and Osteberg Morningness-Eveningness Questionnaires to evaluate chronotype preferences. The chronotype preference of 264 male college students from varied altitude backgrounds indicated significant differences (p < 0.001). Our findings confirm our hypothesis, of the prevalence of M-types dominant chronotype among college students at low than high altitude. However, we did not confirm our second hypothesis, since students from high-altitude backgrounds were generally I-type dominant chronotype. Similarly, students’ academic performances from low- compared to high-altitudes backgrounds also indicated significant differences (p < 0.003). Better academic performances were seen in students with I-type chronotype orientations from high altitudes. 相似文献
5.
Mathivanan Packiarajan Michel Grenon Samuel Zorn Allen T. Hopper Andrew D. White Gamini Chandrasena Xiaosui Pu Robbin M. Brodbeck Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2013,23(14):4037-4043
A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27–31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu5 PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu5 negative allosteric modulators (NAMs). 相似文献
6.
The structure, electron density distribution, energetic and electrostatic properties of simple nitramine based energetic TMA, DMNA, MDA and TNA molecules were determined using density functional theory (B3LYP) with the 6-311G** and aug-cc-pVDZ basis sets coupled with Bader's theory of atoms in molecules. In the NO2 group substituted molecules, the N–N bond distance increases with the increase of NO2 groups, whereas in C–N bonds, this effect is relatively less, and the distances are almost equal. The topological analysis of electron density reveals that the electron density ρbcp(r) of C–N and N–N bonds are significantly decreasing with the increase of NO2 groups in the nitramine molecules. The Laplacian of electron density ▽2ρbcp(r) of N–NO2 bonds [DMNA: ? 16.7 eÅ? 5, MDA: ? 12.8 eÅ? 5 and TNA: ? 7.9 eÅ? 5] of the molecules are relatively less negative, and the values also decrease with the increase of NO2 groups; this implies that the charge concentration decreases with the increase of NO2 groups, which leads to weakening the N–N bonds of the molecules. The isosurface of molecular electrostatic potential displays high electronegative regions around the NO2 groups. The oxygen balance OB100 of the molecules increases as the number of NO2 group increases in the molecules, in which, the TNA molecule having maximum OB100 value [+7.89]. The band gap, heat of detonation, bond dissociation energy and charge imbalance are predominantly depends on the number of NO2 group present in the molecule. The charge imbalance parameter (ν) has been calculated for all molecules, which reveals that TNA is a highly sensitive molecule, the corresponding ν value is 0.047. 相似文献
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Sridhar R Perumal PT Etti S Shanmugam G Ponnuswamy MN Prabavathy VR Mathivanan N 《Bioorganic & medicinal chemistry letters》2004,14(24):6035-6040
In a SAR study, we have synthesized a few 1H-pyrazole carboxylate related microbicides using Vilsmeier reagent. The anti-microbial screening results of 1H-pyrazole-3-carboxylate are reported here for the first time. The effect of 1H-pyrazole carboxylates on the mycelial growth of plant pathogenic fungi is revealed. The first X-ray structure in the family of microbicidal 1H-pyrazole-4-carboxylates is presented. 相似文献
9.
The effect of biogas slurry application on the severity of root-knot nematode, Meloidogyne incognita, attack on tomato cv. Co-1, was tested in the green house with two levels of biogas slurry: 5% and 10% (w/w) added to soil. Both the number (3 fruits/plant) and fruit yield (35.2 g/plant) of tomato increased significantly with 10% (w/w) biogas slurry. The plants amended with biogas slurry put up more vegetative growth and tended to flower and fruit much earlier than did those of the control. The nematode population in the soil decreased thus decreasing the severity of nematode attack. 相似文献
10.
Packiarajan M Marzabadi MR Desai M Lu Y Noble SA Wong WC Jubian V Chandrasena G Wolinsky TD Zhong H Walker MW Wiborg O Andersen K 《Bioorganic & medicinal chemistry letters》2011,21(18):5436-5441
The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress. 相似文献