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91.
Hu W Splith K Neundorf I Merz K Schatzschneider U 《Journal of biological inorganic chemistry》2012,17(2):175-185
Organometallic complexes conjugated to cell-penetrating peptides (CPPs) are promising systems for diagnostic imaging and therapeutic
applications in human medicine. Recently, we reported on the synthesis of cymantrene(CpMn(CO)3)–CPP conjugates with biological activity on different cancer cell lines. However, the precise mechanism of cytotoxicity remained
elusive in these studies. To investigate the role of the metal center and the linker between the CpM(CO)3 moiety and the peptide, a number of derivatives with manganese replaced by rhenium and the keto linker originally used substituted
by a methylene group were prepared and fully characterized by 1H NMR spectroscopy, infrared spectroscopy, electrospray ionization mass spectrometry, and elemental analysis as well as X-ray
structure determination. The organometal–peptide conjugates as well as carboxyfluorescein-labeled derivatives thereof were
prepared by solid-phase peptide synthesis, purified by high-performance liquid chromatography, and analyzed by mass spectrometry.
Fluorescence microscopy studies of MCF-7 human breast cancer cells revealed an efficient cellular uptake and pronounced nuclear
localization of the bioconjugates with the methylene linker compared with systems with the keto group. In addition, the latter
also showed a higher cytotoxicity. In contrast, the variation of the metal center from manganese to rhenium had a negligible
effect. The structure–activity relationships determined in the present work will aid in the further tuning of the biological
activity of organometal–peptide conjugates. 相似文献
92.
Yu N Li X Cui G Hayik SA Merz KM 《Protein science : a publication of the Protein Society》2006,15(12):2773-2784
A critical evaluation of the performance of X-ray refinement protocols using various energy functions is presented using the bovine pancreatic trypsin inhibitor (BPTI) protein. The four potential energy functions we explored include: (1) fully quantum mechanical calculations; (2) one based on an incomplete molecular mechanics (MM) energy function employed in the Crystallography and NMR System (CNS) with empirical parameters developed by Engh and Huber (EH), which lacks electrostatic and attractive van der Waals terms; (3) one based on a complete MM energy function (AMBER ff99 parameter set); and (4) the same as 3, with the addition of a Generalized Born (GB) implicit solvation term. The R, R (free), real space R values of the refined structures and deviations from the original experimental structure were used to assess the relative performance. It was found that at 1 Angstrom resolution the physically based energy functions 1, 3, and 4 performed better than energy function 2, which we attribute to the better representation of key interactions, particularly electrostatics. The observed departures from the experimental structure were similar for the refinements with physically based energy functions and were smaller than the structure refined with EH. A test refinement was also performed with the reflections truncated at a high-resolution cutoff of 2.5 Angstrom and with random perturbations introduced into the initial coordinates, which showed that low-resolution refinements with physically based energy functions held the structure closer to the experimental structure solved at 1 Angstrom resolution than the EH-based refinements. 相似文献
93.
94.
Studies aimed at elucidating the unknown Mg2+ binding site in protein farnesyltransferase (FTase) are reported. FTase catalyzes the transfer of a farnesyl group to a conserved cysteine residue (Cys1p) on a target protein, an important step for proteins in the signal transduction pathways (e.g., Ras). Mg2+ ions accelerate the protein farnesylation reaction by up to 700-fold. The exact function of Mg2+ in catalysis and the structural characteristics of its binding remain unresolved to date. Molecular dynamics (MD) simulations addressing the role of magnesium ions in FTase are presented, and relevant octahedral binding motifs for Mg2+ in wild-type (WT) FTase and the Dβ352A mutant are explored. Our simulations suggest that the addition of Mg2+ ions causes a conformational change to occur in the FTase active site, breaking interactions known to keep FPP in its inactive conformation. Two relevant Mg2+ ion binding motifs were determined in WT FTase. In the first binding motif, WT1, the Mg2+ ion is coordinated to D352β, zinc-bound D297β, two water molecules, and one oxygen atom from the α- and β-phosphates of farnesyl diphosphate (FPP). The second binding motif, WT2, is identical with the exception of the zinc-bound D297β being replaced by a water molecule in the Mg2+ coordination complex. In the Dβ352A mutant Mg2+ binding motif, D297β, three water molecules, and one oxygen atom from the α- and β-phosphates of FPP complete the octahedral coordination sphere of Mg2+. Simulations of WT FTase, in which Mg2+ was replaced by water in the active site, recreated the salt bridges and hydrogen-bonding patterns around FPP, validating these simulations. In all Mg2+ binding motifs, a key hydrogen bond was identified between a magnesium-bound water and Cys1p, bridging the two metallic binding sites and, thereby, reducing the equilibrium distance between the reacting atoms of FPP Cys1p. The free energy profiles calculated for these systems provide a qualitative understanding of experimental results. They demonstrate that the two reactive atoms approach each other more readily in the presence of Mg2+ in WT FTase and mutant. The flexible WT2 model was found to possess the lowest barrier toward the conformational change, suggesting it is the preferred Mg2+ binding motif in WT FTase. In the mutant, the absence of D352β makes the transition toward a conformational change harder. Our calculations find support for the proposal that D352β performs a critical role in Mg2+ binding and Mg2+ plays an important role in the conformational transition step. 相似文献
95.
Glucose is a primary source of energy for human cells. Glucose transporters form specialized membrane channels for the transport of sugars into and out of cells. Galactose permease (GalP) is the closest bacterial homolog of human facilitated glucose transporters. Here, we report the functional reconstitution and 2D crystallization of GalP. Single particle electron microscopy analysis of purified GalP shows that the protein assembles as an oligomer with three distinct densities. Reconstitution assays yield 2D GalP crystals that exhibit a hexagonal array having p3 symmetry. The projection structure of GalP at 18 Å resolution shows that the protein is trimeric. Each monomer in the trimer forms its own channel, but an additional cavity (10∼15 Å in diameter) is apparent at the 3-fold axis of the oligomer. We show that the crystalline GalP is able to selectively bind substrate, suggesting that the trimeric form is biologically active. 相似文献
96.
97.
98.
The sustainability of many research endeavors, particularly in controversial areas, requires an understanding of public concerns. As such, governance strategies should be developed to sustain public trust. 相似文献
99.
Functional dissection of Escherichia coli trigger factor: unraveling the function of individual domains 下载免费PDF全文
Kramer G Rutkowska A Wegrzyn RD Patzelt H Kurz TA Merz F Rauch T Vorderwülbecke S Deuerling E Bukau B 《Journal of bacteriology》2004,186(12):3777-3784
In Escherichia coli, the ribosome-associated chaperone Trigger Factor (TF) promotes the folding of newly synthesized cytosolic proteins. TF is composed of three domains: an N-terminal domain (N), which mediates ribosome binding; a central domain (P), which has peptidyl-prolyl cis/trans isomerase activity and is involved in substrate binding in vitro; and a C-terminal domain (C) with unknown function. We investigated the contributions of individual domains (N, P, and C) or domain combinations (NP, PC, and NC) to the chaperone activity of TF in vivo and in vitro. All fragments comprising the N domain (N, NP, NC) complemented the synthetic lethality of Deltatig DeltadnaK in cells lacking TF and DnaK, prevented protein aggregation in these cells, and cross-linked to nascent polypeptides in vitro. However, DeltatigDeltadnaK cells expressing the N domain alone grew more slowly and showed less viability than DeltatigDeltadnaK cells synthesizing either NP, NC, or full-length TF, indicating beneficial contributions of the P and C domains to TF's chaperone activity. In an in vitro system with purified components, none of the TF fragments assisted the refolding of denatured d-glyceraldehyde-3-phosphate dehydrogenase in a manner comparable to that of wild-type TF, suggesting that the observed chaperone activity of TF fragments in vivo is dependent on their localization at the ribosome. These results indicate that the N domain, in addition to its function to promote binding to the ribosome, has a chaperone activity per se and is sufficient to substitute for TF in vivo. 相似文献
100.
Myotoxin II, a Lys49 catalytically inactive phospholipase A(2) homologue from Atropoides nummifer venom, was purified, characterized and crystallized. The crystals belongs to the tetragonal system, space group P4(3)2(1)2, with unit cell parameters (a=b=68.66 and c=63.87 angstroms). Diffraction data were collected to a resolution of 2.32 angstroms. The crystal structure is currently being determined using molecular replacement techniques. 相似文献