FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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References
Dynamic nuclear polarization of spherical nanoparticles
Akbey, Ü., Altin(*), B., Linden, A., Ozcelik(*), S., Gradzielski(*), M.; Oschkinat, H.
Phys Chem Chem Phys, 15:20706-20716
(2013)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Spherical silica nanoparticles of various particle sizes (~10 to 100 nm), produced by a modified Stoeber method employing amino acids as catalysts, are investigated using Dynamic Nuclear Polarization (DNP) enhanced Nuclear Magnetic Resonance (NMR) spectroscopy. This study includes ultra-sensitive detection of surface-bound amino acids and their supramolecular organization in trace amounts, exploiting the increase in NMR sensitivity of up to three orders of magnitude via DNP. Moreover, the nature of the silicon nuclei on the surface and the bulk silicon nuclei in the core (sub-surface) is characterized at atomic resolution. Thereby, we obtain unique insights into the surface chemistry of these nanoparticles, which might result in improving their rational design as required for promising applications, e.g. as catalysts or imaging contrast agents. The non-covalent binding of amino acids to surfaces was determined which shows that the amino acids not just function as catalysts but become incorporated into the nanoparticles during the formation process. As a result only three distinct Q-types of silica signals were observed from surface and core regions. We observed dramatic changes of DNP enhancements as a function of particle size, and very small particles (which suit in vivo applications better) were hyperpolarized with the best efficiency. Nearly one order of magnitude larger DNP enhancement was observed for nanoparticles with 13 nm size compared to particles with 100 nm size. We determined an approximate DNP penetration-depth (~4.2 or ~5.7 nm) for the polarization transfer from electrons to the nuclei of the spherical nanoparticles. Faster DNP polarization buildup was observed for larger nanoparticles. Efficient hyperpolarization of such nanoparticles, as achieved in this work, can be utilized in applications such as magnetic resonance imaging (MRI).

A Well-Defined Pd Hybrid Material for the Z-Selective Semihydrogenation of Alkynes Characterized at the Molecular Level by DNP SENS
Conley(*), M. P., Drost(*), R. M., Baffert(*), M., Gajan(*), D., Elsevier(*), C., Franks, W. T., Oschkinat, H., Veyre(*), L., Zagdoun(*), A., Rossini(*), A., Lelli(*), M., Lesage(*), A., Casano(*), G., Ouari(*), O., Tordo(*), P., Emsley(*), L., Coperet(*), C.; Thieuleux(*), C.
Chem-Eur J, 19:12234-12238
(2013)

Tags: NMR-Supported Structural Biology (Oschkinat)

The Clip-Segment of the von Willebrand Domain 1 of the BMP Modulator Protein Crossveinless 2 Is Preformed
Fiebig(*), J. E., Weidauer(*), S. E., Qiu(*), L. Y., Bauer(*), M., Schmieder, P., Beerbaum, M., Zhang(*), J. L., Oschkinat, H., Sebald(*), W.; Mueller(*), T. D.
Molecules, 18:11658-11682
(2013)

Tags: NMR-Supported Structural Biology (Oschkinat), Solution NMR (Schmieder)

Abstract: Bone Morphogenetic Proteins (BMPs) are secreted protein hormones that act as morphogens and exert essential roles during embryonic development of tissues and organs. Signaling by BMPs occurs via hetero-oligomerization of two types of serine/threonine kinase transmembrane receptors. Due to the small number of available receptors for a large number of BMP ligands ligand-receptor promiscuity presents an evident problem requiring additional regulatory mechanisms for ligand-specific signaling. Such additional regulation is achieved through a plethora of extracellular antagonists, among them members of the Chordin superfamily, that modulate BMP signaling activity by binding. The key-element in Chordin-related antagonists for interacting with BMPs is the von Willebrand type C (VWC) module, which is a small domain of about 50 to 60 residues occurring in many different proteins. Although a structure of the VWC domain of the Chordin-member Crossveinless 2 (CV2) bound to BMP-2 has been determined by X-ray crystallography, the molecular mechanism by which the VWC domain binds BMPs has remained unclear. Here we present the NMR structure of the Danio rerio CV2 VWC1 domain in its unbound state showing that the key features for high affinity binding to BMP-2 is a pre-oriented peptide loop.

The mechanism of denaturation and the unfolded state of the alpha-helical membrane-associated protein Mistic
Jacso, T., Bardiaux, B., Broecker(*), J., Fiedler(*), S., Baerwinkel(*), T., Mainz, A., Fink, U., Vargas(*), C., Oschkinat, H., Keller(*), S.; Reif, B.
J Am Chem Soc, 135:18884-18891
(2013)

Tags: Solid-State NMR Spectroscopy (Reif), NMR-Supported Structure Biology (Oschkinat)

Abstract: In vitro protein-folding studies using chemical denaturants such as urea are indispensible in elucidating the forces and mechanisms determining the stability, structure, and dynamics of water-soluble proteins. By contrast, alpha-helical membrane-associated proteins largely evade such approaches because they are resilient to extensive unfolding. We have used optical and NMR spectroscopy to provide an atomistic-level dissection of the effects of urea on the structure and dynamics of the alpha-helical membrane-associated protein Mistic as well as its interactions with detergent and solvent molecules. In the presence of the zwitterionic detergent lauryl dimethylamine oxide, increasing concentrations of urea result in a complex sequence of conformational changes that go beyond simple two-state unfolding. Exploiting this finding, we report the first high-resolution structural models of the urea denaturation process of an alpha-helical membrane-associated protein and its completely unfolded state, which contains almost no regular secondary structure but nevertheless retains a topology close to that of the folded state.

A Floquet description of phase alternated sequences for efficient homonuclear recoupling in solid perdeuterated systems
Jayanthi(*), S., Akbey, Ü., Uluca(*), B., Oschkinat, H.; Vega(*), S.
Journal of Magnetic Resonance, 234:10-20
(2013)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: A Floquet description of a phase alternated homonuclear recoupling scheme for perdeuterated systems is presented. As a result, we demonstrate improvements in the recoupling efficiency of the DOuble Nucleus Enhanced Recoupling [DONER; J. Am. Chem. Soc. 131 (2009) 170541 technique by utilizing Phase Alternated Recoupling Irradiation Schemes [PARIS; Chem. Phys. Lett. 469 (2009) 342]. The effect of proton and deuterium radio frequency irradiation during recoupling has been systematically studied and theoretical observations have been verified experimentally using a deuterated model compound, L-Alanine, at 10 and 20 kHz magic angle spinning frequency. Experimental results are well in agreement with theoretical observations, thereby significantly increasing the recoupling efficiency of conventional DONER in perdeuterated systems. (C) 2013 Elsevier Inc. All rights reserved.

Lipophilic prodrugs of a triazole-containing colchicine analogue in liposomes: Biological effects on human tumor cells
Kuznetsova(*), N. R., Svirshchevskaya(*), E. V., Sitnikov(*), N. S., Abodo(*), L., Sutorius(*), H., Zapke, J., Velder(*), J., Thomopoulou(*), P., Oschkinat, H., Prokop(*), A., Schmalz(*), H. G., Fedorov(*), A. Y.; Vodovozova(*), E. L.
Russ J Bioorg Chem+, 39:543-552
(2013)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Colchicine site binders-blockers of tubulin polymerization-are potential antimitotic agents for anticancer therapy. To reduce their systemic toxicity and improve biodistribution, encapsulation in nanosized liposomes may be employed. Liposomes present a convenient means for preparation of injectable for-mulations of hydrophobic compounds, however colchicine as such is known to leak through the lipid bilayer. In this study, newly synthesized triazole-containing analogues of colchicine and allocolchicine, and their palmitic and oleic esters (lipophilic prodrugs) were tested for anti-proliferative activity and apoptosis-inducing potential. In contrast to colchicine conjugates, whose activities ranged with those of colchicine, allocolchicine derivatives exhibited drastically lower effects and were discarded. Liposomes of about 100 nm in diameter composed of egg phosphatidylcholine-yeast phosphatidylinositol-palmitic or oleic prodrug, 8: 1: 1, by mol, were prepared by standard extrusion technique and tested in a panel of four human tumor cell lines. Liposome formulations preserved the biological activities of the parent colchicinoid the most towards human epithelial tumor cells. Moreover, liposomal form of the oleoyl bearing colchicinoid inhibited cell proliferation more efficiently than free lipophilic prodrug. Due to substantial loading capacity of the liposomes, the dispersions contain sufficient concentration of the active agent to test wide dose range in experiments on systemic administration to animals.

Reduced activity of alkaline phosphatase due to host-guest interactions with humic superstructures
Mazzei(*), P., Oschkinat, H.; Piccolo(*), A.
Chemosphere, 93:1972-1979
(2013)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Nuclear Magnetic Resonance (NMR) spectroscopy was applied to directly study the interactions between the alkaline phosphatase enzyme (AP) and two different humic acids from a volcanic soil (HA-V) and a Lignite deposit (HA-L). Addition of humic matter to enzyme solutions caused signals broadening in H-1-NMR spectra, and progressive decrease and increase of enzyme relaxation (T-1 and T-2) and correlation (tau(c)) times, respectively. Spectroscopic changes were explained with formation of ever larger weaklybound humic-enzyme complexes, whose translational and rotational motion was increasingly restricted. NMR diffusion experiments also showed that the AP diffusive properties were progressively reduced with formation of large humic-enzyme complexes. The more hydrophobic HA-L affected spectral changes more than the more hydrophilic HA-V. H-1-NMR spectra also showed the effect of progressively greater humic-enzyme complexes on the hydrolysis of an enzyme substrate, the 4-nitrophenyl phosphate disodium salt hexahydrate (p-NPP). While AP catalysis concomitantly decreased NMR signals of p-NPP and increased those of nitrophenol, addition of humic matter progressively and significantly slowed down the rate of change for these signals. In agreement with the observed spectral changes, the AP catalytic activity was more largely inhibited by HA-L than by HA-V. Contrary to previous studies, in which humic-enzyme interactions were only indirectly assumed from changes in spectrophotometric behavior of enzyme substrates, the direct measurements of AP behavior by NMR spectroscopy indicated that humic materials formed weakly-bound host-guest complexes with alkaline phosphatase, and the enzyme catalytic activity was thereby significantly inhibited. These results suggest that the role of extracellular enzymes in soils may be considerably reduced when they come in contact with organic matter dissolved in the soil solution. (C) 2013 Elsevier Ltd. All rights reserved.

Improved Dynamic Nuclear Polarization Surface-Enhanced NMR Spectroscopy through Controlled Incorporation of Deuterated Functional Groups
Zagdoun(*), A., Rossini(*), A. J., Conley(*), M. P., Grüning(*), W. R., Schwarzwälder(*), M., Lelli(*), M., Franks, W. T., Oschkinat, H., Coperet(*), C., Emsley(*), L.; Lesage(*), A.
Angew Chem Int Edit, 52:1222-1225
(2013)

Tags: NMR-Supported Structural Biology (Oschkinat)

Efficient alpha-helix induction in a linear peptide chain by N-capping with a bridged-tricyclic diproline analogue
Hack(*), V., Reuter(*), C., Opitz, R., Schmieder, P., Beyermann, M., Neudörfl(*), J. M., Kühne, R.; Schmalz(*), H. G.
Angew Chem Int Ed Engl, 52:9539-9543
(2013)

Tags: Solution NMR (Schmieder), Peptide Synthesis (Beyermann), Computational Chemistry/Drug Design (Kühne)

PI4K2beta/AP-1-based TGN-endosomal sorting regulates Wnt signaling
Wieffer, M., Cibrian Uhalte(*), E., Posor, Y., Otten(*), C., Branz, K., Schütz, I., Mössinger, J., Schu(*), P., Abdelilah-Seyfried(*), S., Krauss, M.; Haucke, V.
Curr Biol, 23:2185-2190
(2013)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Endosomal membrane traffic serves crucial roles in cell physiology, signaling, and development. Sorting between endosomes and the trans-Golgi network (TGN) is regulated among other factors by the adaptor AP-1, an essential component of multicellular organisms. Membrane recruitment of AP-1 requires phosphatidylinositol 4-phosphate [PI(4)P], though the precise mechanisms and PI4 kinase isozyme (or isozymes) involved in generation of this PI(4)P pool remain unclear. The Wnt pathway is a major developmental signaling cascade and depends on endosomal sorting in Wnt-sending cells. Whether TGN/endosomal sorting modulates signaling downstream of Frizzled (Fz) receptors in Wnt-receiving cells is unknown. Here, we identify PI4-kinase type 2beta (PI4K2beta) as a regulator of TGN/endosomal sorting and Wnt signaling. PI4K2beta and AP-1 interact directly and are required for efficient sorting between endosomes and the TGN. Zebrafish embryos depleted of PI4K2beta or AP-1 lack pectoral fins due to defective Wnt signaling. Rescue experiments demonstrate requirements for PI4K2beta-AP-1 complex formation and PI4K2beta-mediated PI(4)P synthesis. Furthermore, PI4K2beta binds to the Fz-associated component Dishevelled (Dvl) and regulates endosomal recycling of Fz receptors and Wnt target gene expression. These data reveal an evolutionarily conserved role for PI4K2beta and AP-1 in coupling phosphoinositide metabolism to AP-1-mediated sorting and Wnt signaling.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
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