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91.
The α -toxin (phospholipase C) of Clostridium perfringens has been reported to contain catalytically essential zinc ions We report here that histidine residues are essential for the co-ordination of these ion(s). Incubation of alpha toxin with diethylpyrocarbonate, a histidine modifying reagent, did not result in the loss of phospholipase C activity unless the protein was first incubated with EDTA, suggesting that zinc ions normally protect the susceptible histidine residues. When the amino acid sequences of three phospholipase C's were aligned, essential zinc binding histidine residues in the non-toxic B. cereus phospholipase C were found in similar positions in the toxic C. perfringens enzyme and the weakly toxic C. bifermentans phospholipase C. 相似文献
92.
Tracy A. Stone Gregory B. Cole Huong Q. Nguyen Simon Sharpe Charles M. Deber 《Bioorganic & medicinal chemistry》2018,26(6):1189-1196
Cyclization has been recognized as a valuable technique for increasing the efficacy of small molecule and peptide therapeutics. Here we report the application of a hydrocarbon staple to a rationally-designed cationic antimicrobial peptide (CAP) that acquires increased membrane targeting and interaction vs. its linear counterpart. The previously-described CAP, 6K-F17 (KKKKKK-AAFAAWAAFAA-NH2) was used as the backbone for incorporation of an i to i?+?4 helical hydrocarbon staple through olefin ring closing metathesis. Stapled versions of 6K-F17 showed an increase in non-selective membrane interaction, where the staple itself enhances the degree of membrane interaction and rate of cell death while maintaining high potency against bacterial membranes. However, the higher averaged hydrophobicity imparted by the staple also significantly increases toxicity to mammalian cells. This deleterious effect is countered through stepwise reduction of the stapled 6K-F17’s backbone hydrophobicity through polar amino acid substitutions. Circular dichroism assessment of secondary structure in various bacterial membrane mimetics reveals that a helical structure may improve – but is not an absolute requirement for – antimicrobial activity of 6K-F17. Further, phosphorus-31 static solid state NMR spectra revealed that both non-toxic stapled and linear peptides bind bacterial membranes in a similar manner that does not involve a detergent-like mechanism of lipid removal. The overall results suggest that the technique of hydrocarbon stapling can be readily applied to membrane-interactive CAPs to modulate how they interact and target biological membranes. 相似文献
93.
Integration of molecular dynamics simulation and hotspot residues grafting for de novo scFv design against Salmonella Typhi TolC protein
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Siew Wen Leong Theam Soon Lim Asma Ismail Yee Siew Choong 《Journal of molecular recognition : JMR》2018,31(5)
With the development of de novo binders for protein targets from non‐related scaffolds, many possibilities for therapeutics and diagnostics have been created. In this study, we described the use of de novo design approach to create single‐chain fragment variable (scFv) for Salmonella enterica subspecies enterica serovar Typhi TolC protein. Typhoid fever is a global health concern in developing and underdeveloped countries. Rapid typhoid diagnostics will improve disease management and therapy. In this work, molecular dynamics simulation was first performed on a homology model of TolC protein in POPE membrane bilayer to obtain the central structure that was subsequently used as the target for scFv design. Potential hotspot residues capable of anchoring the binders to the target were identified by docking “disembodied” amino acid residues against TolC surface. Next, scFv scaffolds were selected from Protein Data Bank to harbor the computed hotspot residues. The hotspot residues were then incorporated into the scFv scaffold complementarity determining regions. The designs recapitulated binding energy, shape complementarity, and interface surface area of natural protein‐antibody interfaces. This approach has yielded 5 designs with high binding affinity against TolC that may be beneficial for the future development of antigen‐based detection agents for typhoid diagnostics. 相似文献
94.
Wild bee diversity is enhanced by experimental removal of timber harvest residue within intensively managed conifer forest
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James W. Rivers Codey L. Mathis Andrew R. Moldenke Matthew G. Betts 《Global Change Biology Bioenergy》2018,10(10):766-781
The use of timber harvest residue as an energy source is thought to have environmental benefits relative to food‐based crops, yet the ecological impact of this practice remains largely unknown. We assessed whether the abundance and diversity of wild bees (Apoidea) were influenced by the removal of harvest residue and associated soil compaction within managed conifer forest in western Oregon, USA. We sampled bees over two years (2014–2015) on study plots that were subjected to five treatments representing gradients in removal of harvest residue and soil compaction. We collected >7,500 bee specimens from 92 distinct species/morphospecies that represented five of the seven bee families. We trapped 3x more individuals in the second year of the study despite identical sampling effort in both years, with most trapped bees classified as ground‐nesting species. Members of the sweat bee family (Halictidae) comprised more than half of all specimens, and the most abundant genus was composed of metallic green bees (Agapostemon, 33.6%), followed by long‐horned bees (Melissodes, 16.5%), sweat bees (Halictus, 15.9%), and bumble bees (Bombus, 13.6%). In both years, abundance and observed species richness were greatest in the most intensive harvest residue treatment, with other treatments having similar values for both measures. Our study indicates that early successional managed conifer forest that has experienced removal of harvest residue can harbor a surprising diversity of wild bees, which are likely to have important contributions to the broader ecological community through the pollination services they provide. 相似文献
95.
Intrinsically disordered proteins (IDPs)/regions do not have well‐defined secondary and tertiary structures, however, they are functional and it is critical to gain a deep understanding of their residue packing. The shape distributions methodology, which is usually utilized in pattern recognition, clustering, and classification studies in computer science, may be adopted to study the residue packing of the proteins. In this study, shape distributions of the globular proteins and IDPs were obtained to shed light on the residue packing of their structures. The shape feature that was used is the sphericity of tetrahedra obtained by Delaunay Tessellation of points of Cα coordinates. Then the sphericity probability distributions were compared by using Principal Component Analysis. This computational structural study shows that the set of IDPs constitute a more diverse set than the set of globular proteins in terms of the geometrical properties of their network structures. 相似文献
96.
Nitrogen mineralization and denitrification as influenced by crop residue particle size 总被引:3,自引:1,他引:2
Managing the crop residue particle size has the potential to affect N conservation in agricultural systems. We investigated the influence of barley (Hordeum vulgare) and pea (Pisum sativum) crop residue particle size on N mineralization and denitrification in two laboratory experiments. Experiment 1: 15N-labelled ground (3 mm) and cut (25 mm) barley residue, and microcrystalline cellulose+glucose were mixed into a sandy loam soil with additional inorganic N. Experiment 2: inorganic15 N and C2H2 were added to soils with barley and pea material after 3, 26, and 109 days for measuring gross N mineralization and denitrification.Net N immobilization over 60 days in Experiment 1 cumulated to 63 mg N kg-1 soil (ground barley), 42 (cut barley), and 122 (cellulose+glucose). More N was seemingly net mineralized from ground barley (3.3 mg N kg-1 soil) than from cut barley (2.7 mg N kg-1 soil). Microbial biomass peaked at day 4 with the barley treatments and at day 14 with the cellulose+glucose whereafter the biomass leveled out at values 79 mg C kg-1 (ground), 104 (cut), and 242 (cellulose+glucose) higher than for the control soil. Microbial growth yields were similar for the two barley treatments, ca. 60 mg C g-1 substrate C added, which was lower than the 142 mg C g-1 C added with cellulose+glucose. This suggests that the 75% (w/w) holocelluloses and sugars contained with the barley material remained physically protected despite grinding. In Experiment 2 gross mineralization on day 3 was 4.8 mg N kg-1 d-1 with ground pea, twice as much as for all other treatments. On day 26 the treatment with ground barley had the greatest gross N mineralization. In static cores ground barley denitrified 11-fold more than did cut barley, whereas denitrification was similar for the two pea treatments. In suspensions denitrification was similar for the two treatments both with barley and pea residue.We conclude that the higher microbial activity associated with the initial decomposition of ground plant material is due to a more intimate plant residue-soil contact. On the long term, grinding the plant residues has no significant effect on N dynamics. 相似文献
97.
Benedetti Ettore Iacovino Rosa Pedone Carlo Rossi Filomena Saviano Michele Isernia Carla Montesarchio Daniela de Napoli Lorenzo Piccialli Gennaro 《International journal of peptide research and therapeutics》1997,4(3):129-134
Summary An N- and C-protected derivative ofhomo-β-leucine, Fmoc-homo-β-(S)-leucine methyl ester, synthesized from the corresponding proteinogenic parent α-amino acid in enantiopure form has been
fully characterized in the solid state by X-ray diffraction analysis. The crystal conformation of this new residue indicates
and extended conformation for thishomo-β-residue, with the ϕ torsion angle being more constrained than the μ and ψ angles. 相似文献
98.
《Bioorganic & medicinal chemistry》2016,24(21):5340-5352
γ-Glutamyl transpeptidase (GGT, EC 2.3.2.2) that catalyzes the hydrolysis and transpeptidation of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione metabolism and is an attractive pharmaceutical target. We report here the evaluation of a phosphonate-based irreversible inhibitor, 2-amino-4-{[3-(carboxymethyl)phenoxy](methoyl)phosphoryl}butanoic acid (GGsTop) and its analogues as a mechanism-based inhibitor of human GGT. GGsTop is a stable compound, but inactivated the human enzyme significantly faster than the other phosphonates, and importantly did not inhibit a glutamine amidotransferase. The structure–activity relationships, X-ray crystallography with Escherichia coli GGT, sequence alignment and site-directed mutagenesis of human GGT revealed a critical electrostatic interaction between the terminal carboxylate of GGsTop and the active-site residue Lys562 of human GGT for potent inhibition. GGsTop showed no cytotoxicity toward human fibroblasts and hepatic stellate cells up to 1 mM. GGsTop serves as a non-toxic, selective and highly potent irreversible GGT inhibitor that could be used for various in vivo as well as in vitro biochemical studies. 相似文献
99.
100.
Sarentha Chetty Soumendranath Bhakat Alberto J.M. Martin 《Journal of biomolecular structure & dynamics》2016,34(1):135-151
The PR20 HIV-1 protease, a variant with 20 mutations, exhibits high levels of multi-drug resistance; however, to date, there has been no report detailing the impact of these 20 mutations on the conformational and drug binding landscape at a molecular level. In this report, we demonstrate the first account of a comprehensive study designed to elaborate on the impact of these mutations on the dynamic features as well as drug binding and resistance profile, using extensive molecular dynamics analyses. Comparative MD simulations for the wild-type and PR20 HIV proteases, starting from bound and unbound conformations in each case, were performed. Results showed that the apo conformation of the PR20 variant of the HIV protease displayed a tendency to remain in the open conformation for a longer period of time when compared to the wild type. This led to a phenomena in which the inhibitor seated at the active site of PR20 tends to diffuse away from the binding site leading to a significant change in inhibitor–protein association. Calculating the per-residue fluctuation (RMSF) and radius of gyration, further validated these findings. MM/GBSA showed that the occurrence of 20 mutations led to a drop in the calculated binding free energies (ΔGbind) by ~25.17 kcal/mol and ~5 kcal/mol for p2-NC, a natural peptide substrate, and darunavir, respectively, when compared to wild type. Furthermore, the residue interaction network showed a diminished inter-residue hydrogen bond network and changes in inter-residue connections as a result of these mutations. The increased conformational flexibility in PR20 as a result of loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces led to a loss of protease grip on ligand. It is interesting to note that the difference in conformational flexibility between PR20 and WT conformations was much higher in the case of substrate-bound conformation as compared to DRV. Thus, developing analogues of DRV by retaining its key pharmacophore features will be the way forward in the search for novel protease inhibitors against multi-drug resistant strains. 相似文献