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Institute
- Biochemie und Chemie (158) (remove)
In the title compound, C16H16BrNO4, the dihedral between the planes of the aromatic rings is 7.74 (18)°. The amide group is tilted with respect to the bromo- and methoxy-substituted aromatic rings by 36.3 (8) and 35.2 (8)°, respectively. The meta-methoxy groups are essentially in-plane with the aromatic ring [dihedral angles CH3-O-C-C = -4.6 (4) and -2.5 (4)°]. The para-methoxy group is markedly displaced from the ring plane [dihedral angle CH3-O-C-C = -72.5 (4)°]. The crystal packing is stabilized by N-H...O hydrogen bonds linking the molecules into chains running along the b axis. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.004 Å; R factor = 0.033; wR factor = 0.076; data-to-parameter ratio = 14.6.
4-Chloro-N-m-tolylbenzamide
(2009)
In the title compound, C14H12ClNO, the dihedral angle between the two aromatic rings is 11.29 (15)°. The crystal packing is stabilized by N-H...O hydrogen bonds linking the molecules into chains running along the c axis. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.004 Å; R factor = 0.066; wR factor = 0.178; data-to-parameter ratio = 13.7.
2-Chloro-5-nitroaniline
(2009)
The molecule of the title compound, C6H5ClN2O2, is close to being planar (rms deviation = 0.032 Å for all non-H atoms), with a maximum deviation of -0.107 (3) Å for an O atom. In the crystal structure, intermolecular N-H...O and N-H...N interactions link the molecules into a three-dimensional network. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 A°; R factor = 0.023; wR factor = 0.061; data-to-parameter ratio = 11.8.
The title compound, C21H16N2O2, was derived from 1-(2-hydroxyphenyl)-3-(-methoxyphenyl)propane-1,3-dione. The molecular structure of the title compound is stabilized by an intramolecular O-H...N hydrogen bond. The dihedral angle between the hydroxyphenyl ring involved in this intramolecular hydrogen bond and the pyrazole ring is significantly smaller [10.07 (6)°] than the dihedral angle between the pyrazole and the other hydroxyphenyl ring [36.64 (5)°]. The benzene ring makes a dihedral angle of 54.95 (3)° with the pyrazole ring. The crystal packing is stabilized by O-H...O and O-H...N hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.039; wR factor = 0.101; data-to-parameter ratio = 16.2.
In the molecule of the title compound, C14H16ClN3O, the benzene and pyrazole rings are oriented at a dihedral angle of 3.50 (3)°. In the crystal structure, intermolecular N-H...O hydrogen bonds link the molecules into chains. A [pi]-[pi] contact between the benzene and pyrazole rings [centroid-centroid distance = 3.820 (3) Å] may further stabilize the structure. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.031; wR factor = 0.086; data-to-parameter ratio = 14.1.
Orthopoxviruses are large DNA viruses that replicate within the cytoplasm of infected cells encoding over a hundred different proteins. The orthopoxviral 68k ankyrin‐like protein (68k‐ank) is highly conserved among orthopoxviruses, and this study aimed at elucidating the function of 68k‐ank. The 68k‐ank protein is composed of four ankyrin repeats (ANK) and an F‐box‐like domain; both motifs are known proteinprotein interaction domains. The F‐box is found in cellular F‐box proteins (FBP), crucial components of cellular E3 ubiquitin (Ub) ligases. With yeast‐two‐hybrid screens and subsequent co‐immunoprecipitation analyses, it was possible to identify S‐phase kinase‐associated protein 1a (Skp1a) as a cellular counterpart of 68k‐ank via binding to the F‐box‐like domain. Additionally, Cullin‐1 was co‐precipitated, suggesting the formation of a viral‐cellular SCF E3 Ub ligase complex. Modified Vaccinia virus Ankara (MVA) ‐ being attenuated and unable to replicate in most mammalian cell lines due to a block in morphogenesis – nevertheless, expresses its complete genetic information attributing to its properties as promising vector vaccine. Conservation of 68k‐ank as the only ANK protein encoded by MVA implied a substantial role of this viral factor. Hence, its function in the viral life cycle was assessed by studying a 68k‐ank knock‐out MVA. A mutant phenotype manifested in nonpermissive mammalian cells characterized by a block succeeding viral early gene expression and by a reduced ability of the virus to shutoff host protein synthesis. Studies with MVA encoding a 68k‐ank F‐box‐like domain truncated protein revealed that viral‐cellular SCF complex formation and maintenance of viral gene expression are two distinct, unrelated functions fulfilled by 68k‐ank. Moreover, K1, a well‐described VACV host range factor of the ANK protein family, is able to complement 68k‐ank function. This suggests that gene expression of MVA putatively depends on the ANKs encoded in 68k‐ank. In addition to the important findings in vitro, first virulence studies with the mouse pox agent, ectromelia virus (ECTV) deleted of the 68k‐ank ortholog (C11) suggested that this factor contributes to ECTV virulence in vivo.
The transporter associated with antigen processing-like (TAPL) acts as a lysosomal ATP-dependent polypeptide transporter with broad length selectivity. To characterize in detail its substrate specificity, a procedure for solubilization, purification and functional reconstitution of human TAPL was developed. TAPL was expressed in Sf9 insect cells with the baculovirus expression system and solubilized from crude membranes. By intensive screening of detergents, the mild non-ionic detergents digitonin and dodecylmaltoside were found to be ideal for solubilization with respect to efficiency, long term stability, and functionality of TAPL. TAPL was isolated in a two-step procedure with a yield of 500 micro g/L cell culture and, subsequently, reconstituted into proteoliposomes. The KM(pep) for the peptide RRYCfKSTEL (f refers to fluorescence label) and KM(ATP) were determined to be 10.5 ± 2.3 micro M and 97.6 ± 27.5 micro M, respectively, which are in the same range as the Michaelis-Menten constants determined in the membranes. The peptide transport activity of the reconstituted TAPL strongly depends on the lipid composition. Interestingly, the E. coli lipids are prefered over other tested natural lipids extracts. Moreover, phosphatidylcholine, the most abundant phospholipid in eukaryotic cells influenced TAPL activity in a dose dependent manner. In addition, some negatively charged lipids like DOPA and DOPS increased peptide transport activity with preference for DOPS. However, DOPE or egg PG which are also negatively charged had no effect. It seems not only the charge but also the specific head group of phospholipids that has impact on the function of TAPL. With the help of combinatorial peptide libraries containing D-amino acid residues at defined positions as well as bulky fluorescein labeled peptides, the key positions of the peptides were localized to the N- and C-terminal residues with respect to peptide transport. The C-terminal position has the strongest selectivity since modification at this position shows strongest impact on peptide transport. Additionally, positions 2 and 3 of the peptide also have weak influence on peptide selectivity. Subsequently, the residue preferences at the key positions were systematically investigated by combinatorial peptide libraries with defined residues at certain positions. At both ends, TAPL favors positively charged, aromatic, or hydrophobic residues and disfavors negatively charged residues as well as asparagine and methionine. The residue preferences at the key positions are valid for peptide substrates with different length, indicating a general rule for TAPL selectivity. Besides specific interactions of both terminal residues, electrostatic interactions are important, since peptides with positive net charge are more efficiently transported than negatively charged ones. By size exclusion chromatography (SEC) and blue native PAGE, TAPL purified in the presence of digitonin or dodecylmaltoside had an apparent molecular weight of 200 kDa which is close to the theoretical molecular mass of the TAPL homodimer (172 kDa). The purified and reconstituted TAPL showed specific ATP hydrolysis activity which can be inhibited by orthovanadate. TAPL in proteoliposomes showed 6-fold higher ATP hydrolysis than digitonin solubilized protein, indicating the phospholipids impact on TAPL function. However, no peptide substrate stimulated ATPase activity was observed. For site-specific labeling of TAPL, eight cysteines in each half transporter were replaced by alanine or valine. The TAPL cys-less mutant showed the same peptide transport activity as TAPL wt. Based on the functional TAPL cys-less mutant, seven single cysteine mutants were introduced into strategic positions. All single cysteine mutants in the TMD did not influence peptide transport, whereas the mutant L701C, which is close to the conserved H-loop motif, displayed impaired transport. TAPL orthologs Haf-4 and Haf-9 from Caenorhabditis elegans possess around 40% sequence identities with TAPL and 50% with each other. Both proteins are putative half transporters and reported to be involved in the intestinal granule formation (Bauer, 2006; Kawai et al., 2009). To further understand the physiological functions of these two proteins, they were expressed in Sf9 insect cells. Haf-4 and Haf-9 showed weak but specific ATP- and peptide-dependent peptide transport activity for the given peptide RRYCfKSTEL. Therefore, it was proposed that the physiological roles for Haf-4 and Haf-9 might be related to their peptide transport activity. Besides forming functional homodimeric complex as estimated by the peptide transport activities, both half transporter could also form heteromers which was confirmed by coimmunoprecipitation. However, the heteromers showed decreased transport activity.
Modelling protein flexibility and plasticity is computationally challenging but important for understanding the function of biological systems. Furthermore, it has great implications for the prediction of (macro) molecular complex formation. Recently, coarse-grained normal mode approaches have emerged as efficient alternatives for investigating large-scale conformational changes for which more accurate methods like MD simulation are limited due to their computational burden. We have developed a Normal Mode based Simulation (NMSim) approach for efficient conformation generation of macromolecules. Combinations of low energy normal modes are used to guide a simulation pathway, whereas an efficient constraints correction approach is applied to generate stereochemically allowed conformations. Non-covalent bonds like hydrogen bonds and hydrophobic tethers and phi-psi favourable regions are also modelled as constraints. Conformations from our approach were compared with a 10 ns MD trajectory of lysozyme. A 2-D RMSD plot shows a good overlap of conformational space, and rms fluctuations of residues show a correlation coefficient of 0.78 between the two sets of conformations. Furthermore, a comparison of NMSim simulations starting from apo structures of different proteins show that ligand-bound conformations can be sampled for those cases where conformational changes are mainly correlated, e.g., domain-like motion in adenylate kinase. Efforts are currently being made to also model localized but functionally important motions for protein binding pockets and protein-protein interfaces using relevant normal mode selection criteria and implicit rotamer basin creation.
We have investigated the role of reactive oxygen species and thiol-oxidizing agents in the induction of cell death and have shown that adenocarcinoma gastric (AGS) cells respond differently to the oxidative challenge according to the signaling pathways activated. In particular, apoptosis in AGS cells is induced via the mitochondrial pathway upon treatment with thiol-oxidizing agents, such as diamide. Apoptosis is associated with persistent oxidative damage, as evidenced by the increase in carbonylated proteins and the expression/activation of DNA damage-sensitive proteins histone H2A.X and DNA-dependent protein kinase. Resistance to hydrogen peroxide is instead associated with Keap1 oxidation and rapid translocation of Nrf2 into the nucleus. Sensitivity to diamide and resistance to hydrogen peroxide are correlated with GSH redox changes, with diamide severely increasing GSSG, and hydrogen peroxide transiently inducing protein-GSH mixed disulfides. We show that p53 is activated in response to diamide treatment by the oxidative induction of the Trx1/p38(MAPK) signaling pathway. Similar results were obtained with another carcinoma cell line, CaCo2, indicating that these findings are not limited to AGS cells. Our data suggest that thiol-oxidizing agents could be exploited as inducers of apoptosis in tumor histotypes resistant to ROS-producing chemotherapeutics.
Macrophages ingesting apoptotic cells attenuate inflammatory responses, such as reactive oxygen species (ROS) generation. In atherosclerosis, ongoing inflammation and accumulation of apoptotic/necrotic material are observed, suggesting defects of phagocytes in recognizing or responding to dying cells. Modified lipoproteins such as oxidized LDL (oxLDL) are known to promote inflammation and to interfere with apoptotic cell clearance. Here, we studied the impact of cells exposed to oxLDL on their ability to interfere with the oxidative burst in phagocytes. In contrast to apoptotic cells, cells dying in response to or in the presence of oxLDL failed to suppress ROS generation despite efficiently being taken up by phagocytes. In addition, apoptotic cells, but not oxLDL-treated cells, inhibited phosphorylation of extracellular signal-regulated kinase, which is important for NADPH oxidase activation. oxLDL treatment did not interfere with activation of the antiinflammatory transcriptional regulator peroxisome proliferator-activated receptor gamma by apoptotic cells. Moreover, cells exposed to oxLDL failed to suppress lipopolysaccharide- induced proinflammatory cytokine expression, whereas apoptotic cells attenuated these phagocyte responses. Thus, the presence of oxLDL during cell death impaired the ability of apoptotic cells to act antiinflammatory with regard to oxidative burst inhibition and cytokine expression in phagocytes.