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Sahoo BR Swain B Basu M Panda P Maiti NK Samanta M 《Journal of molecular modeling》2012,18(5):1713-1722
Interleukin-10 (IL-10) is a pleiotropic immune-regulatory cytokine that is expressed in various species of fish and higher
vertebrates, and is activated during infection. In spite of its important role, IL-10 has not been well characterized either
functionally or structurally in fish. To analyze its properties and function, we constructed a 3D model of IL-10 in the Indian
major carp, the catla (Catla catla), which is a highly preferred fish species and the most commercially important one in the Indian subcontinent. The catla
IL-10 model was constructed by comparative modeling using human IL-10 (2ILK) as the template, and a 5 ns molecular dynamics
(MD) simulation was carried out to characterize its structural and dynamical features, which was validated by the SAVES, WHAT
IF and MolProbity servers. Analysis using the VAST server revealed a comparatively low level of homology between catla and
human IL-10 amino acids at the N-terminal (22.7%) compared to the C-terminal (38.29%). Six conserved domains (A–F) were predicted
in catla that threaded well with human IL-10, but their putative interaction sites varied significantly. The amino acid residues
in helices A and F differed in length between catla and human IL-10, which may lead to the differences in the IL-10/IL-10R
complexes of these two species. The existence of two highly conserved amino acid residues (Cys5 and Cys10) in fish IL-10 but
not in higher vertebrate (including human) IL-10 was analyzed in this 3D model. CastP, cons-PPISP and InterProSurf server
identified several binding pockets with various probe radii, but Cys5 and Cys10 did not form any significant bonds relating
to structural stabilization or protein–protein interactions. 相似文献
75.
Selenium as a novel regulator of porphyrin biosynthesis in germinating seedlings of mung bean (Phaseolus vulgaris) 总被引:1,自引:0,他引:1
5-Aminolevulinic acid, porphyrin and chlorophyll contents as well the activities of 5-aminolevulinic acid dehydratase and PBG deaminase were studied in selenium treated mung bean seedlings. Selenium had no effect on 5-aminolevulinic acid synthetic ability but inhibited 5-aminolevulinic acid dehydratase and PBG deaminase activities. Further, it was observed that selenium induced accumulation of protoporphyrin-IX and Mg-protoporphyrin ester and decreased chlorophyll levels in both light and dark-grown seedlings. The results suggest the possible regulatory role of selenium on chlorophyll synthesis by interacting with sulfhydryl containing enzymes 5-aminolevulinic acid dehydratase and porphobilinogen deaminase. 相似文献
76.
Li H Gade P Nallar SC Raha A Roy SK Karra S Reddy JK Reddy SP Kalvakolanu DV 《The Journal of biological chemistry》2008,283(19):13077-13086
77.
Nine‐day‐old Spodoptera litura (Fab.) larvae were treated with crude destruxin (dtx) extracted from a high‐virulent (M‐19) and a low‐virulent (M‐10) isolate of the entomopathogenic fungus, Metarhizium anisopliae (Metch.), at doses that caused 30%, 50% and 90% mortality in the treated groups after 48 h. Destruxins produced a dose‐dependent decrease in the body weight of the larvae after 1, 24 and 48 h of treatment. There was a considerable hike in the activity of lipoxygenase and lipid peroxidation levels in the treated larvae with increased time of exposure to mycotoxin. The activities of total superoxide dismutase, total catalase, total peroxidase and specific ascorbate peroxidase in the larval body also registered alterations in the dtx‐treated larvae, suggesting that exposure of larvae to crude dtx induces oxidative stress which is countered by the antioxidant enzymes to an extent governed by the concentration and time of treatment, beyond which the larvae succumb to the ecofriendly biotoxin. 相似文献
78.
Saito H Dhanasekaran P Nguyen D Holvoet P Lund-Katz S Phillips MC 《The Journal of biological chemistry》2003,278(26):23227-23232
Detailed structural information on human exchangeable apolipoproteins (apo) is required to understand their functions in lipid transport. Using a series of deletion mutants that progressively lacked different regions along the molecule, we probed the structural organization of lipid-free human apoA-I and the role of different domains in lipid binding, making comparisons to apoE, which is a member of the same gene family and known to have two structural domains. Measurements of alpha-helix content by CD in conjunction with tryptophan and 8-anilino-1-naphthalenesulfonic acid fluorescence data demonstrated that deletion of the amino-terminal or central regions disrupts the tertiary organization, whereas deletion of the carboxyl terminus has no effect on stability and induces a more cooperative structure. These data are consistent with the lipid-free apoA-I molecule being organized into two structural domains similar to apoE; the amino-terminal and central parts form a helix bundle, whereas the carboxyl-terminal alpha-helices form a separate, less organized structure. The binding of the apoA-I variants to lipid emulsions is modulated by reorganization of the helix bundle structure, because the rate of release of heat on binding is inversely correlated with the stability of the helix bundle. Based on these observations, we propose that there is a two-step mechanism for lipid binding of apoA-I: apoA-I initially binds to a lipid surface through amphipathic alpha-helices in the carboxyl-terminal domain, followed by opening of the helix bundle in the amino-terminal domain. Because apoE behaves similarly, this mechanism is probably a general feature for lipid interaction of other exchangeable apolipoproteins, such as apoA-IV. 相似文献
79.
Luo P Hayes RJ Chan C Stark DM Hwang MY Jacinto JM Juvvadi P Chung HS Kundu A Ary ML Dahiyat BI 《Protein science : a publication of the Protein Society》2002,11(5):1218-1226
Granulocyte-colony stimulating factor (G-CSF) is used worldwide to prevent neutropenia caused by high-dose chemotherapy. It has limited stability, strict formulation and storage requirements, and because of poor oral absorption must be administered by injection (typically daily). Thus, there is significant interest in developing analogs with improved pharmacological properties. We used our ultrahigh throughput computational screening method to improve the physicochemical characteristics of G-CSF. Improving these properties can make a molecule more robust, enhance its shelf life, or make it more amenable to alternate delivery systems and formulations. It can also affect clinically important features such as pharmacokinetics. Residues in the buried core were selected for optimization to minimize changes to the surface, thereby maintaining the active site and limiting the designed protein's potential for antigenicity. Using a structure that was homology modeled from bovine G-CSF, core designs of 25-34 residues were completed, corresponding to 10(21)-10(28) sequences screened. The optimal sequence from each design was selected for biophysical characterization and experimental testing; each had 10-14 mutations. The designed proteins showed enhanced thermal stabilities of up to 13 degrees C, displayed five-to 10-fold improvements in shelf life, and were biologically active in cell proliferation assays and in a neutropenic mouse model. Pharmacokinetic studies in monkeys showed that subcutaneous injection of the designed analogs results in greater systemic exposure, probably attributable to improved absorption from the subcutaneous compartment. These results show that our computational method can be used to develop improved pharmaceuticals and illustrate its utility as a powerful protein design tool. 相似文献
80.
Mizuguchi C Hata M Dhanasekaran P Nickel M Phillips MC Lund-Katz S Saito H 《Biochemistry》2012,51(28):5580-5588
Apolipoprotein (apo) E is thought to undergo conformational changes in the N-terminal helix bundle domain upon lipid binding, modulating its receptor binding activity. In this study, site-specific fluorescence labeling of the N-terminal (S94) and C-terminal (W264 or S290) helices in apoE4 by pyrene maleimide or acrylodan was employed to probe the conformational organization and lipid binding behavior of the N- and C-terminal domains. Guanidine denaturation experiments monitored by acrylodan fluorescence demonstrated the less organized, more solvent-exposed structure of the C-terminal helices compared to the N-terminal helix bundle. Pyrene excimer fluorescence together with gel filtration chromatography indicated that there are extensive intermolecular helix-helix contacts through the C-terminal helices of apoE4. Comparison of increases in pyrene fluorescence upon binding of pyrene-labeled apoE4 to egg phosphatidylcholine small unilamellar vesicles suggests a two-step lipid-binding process; apoE4 initially binds to a lipid surface through the C-terminal helices followed by the slower conformational reorganization of the N-terminal helix bundle domain. Consistent with this, fluorescence resonance energy transfer measurements from Trp residues to acrylodan attached at position 94 demonstrated that upon binding to the lipid surface, opening of the N-terminal helix bundle occurs at the same rate as the increase in pyrene fluorescence of the N-terminal domain. Such a two-step mechanism of lipid binding of apoE4 is likely to apply to mostly phospholipid-covered lipoproteins such as VLDL. However, monitoring pyrene fluorescence upon binding to HDL(3) suggests that not only apoE-lipid interactions but also protein-protein interactions are important for apoE4 binding to HDL(3). 相似文献