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91.
Emre Brookes Borries Demeler Camillo Rosano Mattia Rocco 《European biophysics journal : EBJ》2010,39(3):423-435
The interpretation of solution hydrodynamic data in terms of macromolecular structural parameters is not a straightforward
task. Over the years, several approaches have been developed to cope with this problem, the most widely used being bead modeling
in various flavors. We report here the implementation of the SOMO (SOlution MOdeller; Rai et al. in Structure 13:723–734,
2005) bead modeling suite within one of the most widely used analytical ultracentrifugation data analysis software packages, UltraScan
(Demeler in Modern analytical ultracentrifugation: techniques and methods, Royal Society of Chemistry, UK, 2005). The US-SOMO version is now under complete graphical interface control, and has been freed from several constraints present
in the original implementation. In the direct beads-per-atoms method, virtually any kind of residue as defined in the Protein
Data Bank (e.g., proteins, nucleic acids, carbohydrates, prosthetic groups, detergents, etc.) can be now represented with
beads whose number, size and position are all defined in user-editable tables. For large structures, a cubic grid method based
on the original AtoB program (Byron in Biophys J 72:408–415, 1997) can be applied either directly on the atomic structure, or on a previously generated bead model. The hydrodynamic parameters
are then computed in the rigid-body approximation. An extensive set of tests was conducted to further validate the method,
and the results are presented here. Owing to its accuracy, speed, and versatility, US-SOMO should allow to fully take advantage
of the potential of solution hydrodynamics as a complement to higher resolution techniques in biomacromolecular modeling. 相似文献
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93.
Irene Zubiri Vittoria Lombardi Michael Bremang Vikram Mitra Giovanni Nardo Rocco Adiutori Ching-Hua Lu Emanuela Leoni Ping Yip Ozlem Yildiz Malcolm Ward Linda Greensmith Caterina Bendotti Ian Pike Andrea Malaspina 《Molecular neurodegeneration》2018,13(1):60
Background
It is unclear to what extent pre-clinical studies in genetically homogeneous animal models of amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disorder, can be informative of human pathology. The disease modifying effects in animal models of most therapeutic compounds have not been reproduced in patients. To advance therapeutics in ALS, we need easily accessible disease biomarkers which can discriminate across the phenotypic variants observed in ALS patients and can bridge animal and human pathology. Peripheral blood mononuclear cells alterations reflect the rate of progression of the disease representing an ideal biological substrate for biomarkers discovery.Methods
We have applied TMTcalibrator?, a novel tissue-enhanced bio fluid mass spectrometry technique, to study the plasma proteome in ALS, using peripheral blood mononuclear cells as tissue calibrator. We have tested slow and fast progressing SOD1G93A mouse models of ALS at a pre-symptomatic and symptomatic stage in parallel with fast and slow progressing ALS patients at an early and late stage of the disease. Immunoassays were used to retest the expression of relevant protein candidates.Results
The biological features differentiating fast from slow progressing mouse model plasma proteomes were different from those identified in human pathology, with only processes encompassing membrane trafficking with translocation of GLUT4, innate immunity, acute phase response and cytoskeleton organization showing enrichment in both species. Biological processes associated with senescence, RNA processing, cell stress and metabolism, major histocompatibility complex-II linked immune-reactivity and apoptosis (early stage) were enriched specifically in fast progressing ALS patients. Immunodetection confirmed regulation of the immunosenescence markers Galectin-3, Integrin beta 3 and Transforming growth factor beta-1 in plasma from pre-symptomatic and symptomatic transgenic animals while Apolipoprotein E differential plasma expression provided a good separation between fast and slow progressing ALS patients.Conclusions
These findings implicate immunosenescence and metabolism as novel targets for biomarkers and therapeutic discovery and suggest immunomodulation as an early intervention. The variance observed in the plasma proteomes may depend on different biological patterns of disease progression in human and animal model.94.
Maurizio D'Auria Lucia Emanuele Rocco Racioppi 《Photochemical & photobiological sciences》2004,3(10):927-932
The photochemical reaction of 1-(2-furyl)-1-phenylethanol with benzaldehyde gave a mixture of regioisomeric products. The adduct obtained on the more hindered side of the molecule was obtained with complete diastereoselectivity. The same substrate with benzophenone gave only one product with a diastereoisomeric excess of 48%. The reaction of 2-(2-furyl)-3,3-dimethylbutan-2-ol with benzaldehyde and benzophenone gave the corresponding adducts on the more hindered side of the molecule with diastereoisomeric excesses of 42 and 71%, respectively. These results, and also those obtained using 2-furylphenylmethanol with benzophenone and acetone (complete diastereoselectivity and absence of diastereoselectivity, respectively), were explained assuming the attack of the excited carbonyl compound on the same side as the hydroxy group, through the formation of a hydrogen bond or of a complex. This type of attack gave the biradical intermediate in preferential conformations. The relative energies of these conformers account for the observed diastereoselectivity. 相似文献
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98.
Structure of the catalytic domain of human polo-like kinase 1 总被引:2,自引:0,他引:2
Kothe M Kohls D Low S Coli R Cheng AC Jacques SL Johnson TL Lewis C Loh C Nonomiya J Sheils AL Verdries KA Wynn TA Kuhn C Ding YH 《Biochemistry》2007,46(20):5960-5971
Polo-like kinase 1 (Plk1) is an attractive target for the development of anticancer agents due to its importance in regulating cell-cycle progression. Overexpression of Plk1 has been detected in a variety of cancers, and expression levels often correlate with poor prognosis. Despite high interest in Plk1-targeted therapeutics, there is currently no structure publicly available to guide structure-based drug design of specific inhibitors. We determined the crystal structures of the T210V mutant of the kinase domain of human Plk1 complexed with the nonhydrolyzable ATP analogue adenylylimidodiphosphate (AMPPNP) or the pyrrolo-pyrazole inhibitor PHA-680626 at 2.4 and 2.1 A resolution, respectively. Plk1 adopts the typical kinase domain fold and crystallized in a conformation resembling the active state of other kinases. Comparison of the kinetic parameters determined for the (unphosphorylated) wild-type enzyme, as well as the T210V and T210D mutants, shows that the mutations primarily affect the kcat of the reaction, with little change in the apparent Km for the protein or nucleotide substrates (kcat = 0.0094, 0.0376, and 0.0049 s-1 and Km(ATP) = 3.2, 4.0, and 3.0 microM for WT, T210D, and T210V, respectively). The structure highlights features of the active site that can be exploited to obtain Plk1-specific inhibitors with selectivity over other kinases and Plk isoforms. These include the presence of a phenylalanine at the bottom of the ATP pocket, combined with a cysteine (as opposed to the more commonly found leucine) in the roof of the binding site, a pocket created by Leu132 in the hinge region, and a cluster of positively charged residues in the solvent-exposed area outside of the adenine pocket adjacent to the hinge region. 相似文献
99.
Control of Pratylenchus brachyurus in soybean with Trichoderma spp. and resistance inducers
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Juliana Kath Cláudia R. Dias‐Arieira Júlio César Antunes Ferreira Juliana Aparecida Homiak Camila Rocco da Silva Carine Rezende Cardoso 《Journal of Phytopathology》2017,165(11-12):791-799
Trichoderma spp. is a fungus with nematode control potential; however, its potential to control the root lesion nematode Pratylenchus brachyurus remains poorly studied. Thus, the aim of this study was to select Trichoderma spp. isolates and assess their ability to control P. brachyurus in soybean crops. Different experiments were conducted aiming at selecting isolates, assessing whether they were able to reduce nematode penetration in plants or cause mortality in vitro, and whether they were able to induce resistance in soybean, as well as at studying the possibility of using the selected isolates associated with resistance inducers (acibenzolar‐S‐methyl, Ecolife? and AgroMos?). The selection experiment found three isolates showing satisfactory results, namely GF422, GF425 and GF427; the GF362 isolate was assessed in the subsequent experiments. These four isolates reduced P. brachyurus penetration in soybean roots and promoted nematode mortality in vitro. Increased total protein and catalase activity were recorded, mainly in the 72‐hr assessments. Overall, the protein production was different between isolates. The best results were found in the combination between the GF362 isolate and the three resistance inducers, between GF427 and Ecolife?, between GF427 and AgroMos? and between GF422 and Ecolife?. 相似文献
100.
Hantgan RR Stahle MC Connor JH Horita DA Rocco M McLane MA Yakovlev S Medved L 《Protein science : a publication of the Protein Society》2006,15(8):1893-1906
This study tested the hypothesis that high-affinity binding of macromolecular ligands to the alphaIIbbeta3 integrin is tightly coupled to binding-site remodeling, an induced-fit process that shifts a conformational equilibrium from a resting toward an open receptor. Interactions between alphaIIbbeta3 and two model ligands-echistatin, a 6-kDa recombinant protein with an RGD integrin-targeting sequence, and fibrinogen's gamma-module, a 30-kDa recombinant protein with a KQAGDV integrin binding site-were measured by sedimentation velocity, fluorescence anisotropy, and a solid-phase binding assay, and modeled by molecular graphics. Studying echistatin variants (R24A, R24K, D26A, D26E, D27W, D27F), we found that electrostatic contacts with charged residues at the alphaIIb/beta3 interface, rather than nonpolar contacts, perturb the conformation of the resting integrin. Aspartate 26, which interacts with the nearby MIDAS cation, was essential for binding, as D26A and D26E were inactive. In contrast, R24K was fully and R24A partly active, indicating that the positively charged arginine 24 contributes to, but is not required for, integrin recognition. Moreover, we demonstrated that priming--i.e., ectodomain conformational changes and oligomerization induced by incubation at 35 degrees C with the ligand-mimetic peptide cHarGD--promotes complex formation with fibrinogen's gamma-module. We also observed that the gamma-module's flexible carboxy terminus was not required for alphaIIbbeta3 integrin binding. Our studies differentiate priming ligands, which bind to the resting receptor and perturb its conformation, from regulated ligands, where binding-site remodeling must first occur. Echistatin's binding energy is sufficient to rearrange the subunit interface, but regulated ligands like fibrinogen must rely on priming to overcome conformational barriers. 相似文献