FMP Publications

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

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References
Green tea reduces body fat via upregulation of neprilysin
Muenzner, M., Tappenbeck(*), N., Gembardt(*), F., Rülke, R., Furkert, J., Melzig(*), M. F., Siems, W. E., Brockmann(*), G. A.; Walther(*), T.
Int J Obes (Lond), 40:1850-1855
(2016)

Tags: Biochemical Neurobiology (Siems)

Abstract: BACKGROUND/OBJECTIVE: Consumption of green tea has become increasingly popular, particularly because of claimed reduction in body weight. We recently reported that animals with pharmacological inhibition (by candoxatril) or genetic absence of the endopeptidase neprilysin (NEP) develop an obese phenotype. We now investigated the effect of green tea extract (in drinking water) on body weight and body composition and the mediating role of NEP. SUBJECTS/METHODS: To elucidate the role of NEP in mediating the beneficial effects of green tea extract, 'Berlin fat mice' or NEP-deficient mice and their age- and gender-matched wild-type controls received the extract in two different doses (300 or 600 mg kg-1 body weight per day) in the drinking water. RESULTS: In 'Berlin fat mice', 51 days of green tea treatment did not only prevent fat accumulation (control: day 0: 30.5% fat, day 51: 33.1%; NS) but also reduced significant body fat (green tea: day 0: 27.8%, day 51: 20.9%, P<0.01) and body weight below the initial levels. Green tea reduced food intake. This was paralleled by a selective increase in peripheral (in kidney 17%, in intestine 92%), but not central NEP expression and activity, leading to downregulation of orexigens (like galanin and neuropeptide Y (NPY)) known to be physiological substrates of NEP. Consequently, in NEP-knockout mice, green tea extract failed to reduce body fat/weight. CONCLUSIONS: Our data generate experimental proof for the assumed effects of green tea on body weight and the key role for NEP in such process, and thus open a new avenue for the treatment of obesity.

AKAP18:PKA-RIIalpha structure reveals crucial anchor points for recognition of regulatory subunits of PKA
Götz, F., Roske(*), Y., Schulz(*), M. S., Autenrieth(*), K., Bertinetti(*), D., Faelber(*), K., Zühlke(*), K., Kreuchwig, A., Kennedy(*), E. J., Krause, G., Daumke(*), O., Herberg(*), F. W., Heinemann(*), U.; Klussmann(*), E.
Biochem J, 473:1881-1894
(2016)

Tags: Structural Bioinformatics and Protein Design (Krause, G.), Anchored Signaling (Klussmann)

Abstract: A-kinase anchoring proteins (AKAPs) interact with the dimerization/docking (D/D) domains of regulatory subunits of the ubiquitous protein kinase A (PKA). AKAPs tether PKA to defined cellular compartments establishing distinct pools to increase the specificity of PKA signalling. Here, we elucidated the structure of an extended PKA-binding domain of AKAP18beta bound to the D/D domain of the regulatory RIIalpha subunits of PKA. We identified three hydrophilic anchor points in AKAP18beta outside the core PKA-binding domain, which mediate contacts with the D/D domain. Such anchor points are conserved within AKAPs that bind regulatory RII subunits of PKA. We derived a different set of anchor points in AKAPs binding regulatory RI subunits of PKA. In vitro and cell-based experiments confirm the relevance of these sites for the interaction of RII subunits with AKAP18 and of RI subunits with the RI-specific smAKAP. Thus we report a novel mechanism governing interactions of AKAPs with PKA. The sequence specificity of each AKAP around the anchor points and the requirement of these points for the tight binding of PKA allow the development of selective inhibitors to unequivocally ascribe cellular functions to the AKAP18-PKA and other AKAP-PKA interactions.

High resolution observed in 800 MHz DNP spectra of extremely rigid type III secretion needles
Fricke, P., Mance(*), D., Chevelkov, V., Giller(*), K., Becker(*), S., Baldus(*), M.; Lange, A.
J Biomol NMR, 65:121-126
(2016)

Tags: Molecular Biophysics (Lange, A.)

Abstract: The cryogenic temperatures at which dynamic nuclear polarization (DNP) solid-state NMR experiments need to be carried out cause line-broadening, an effect that is especially detrimental for crowded protein spectra. By increasing the magnetic field strength from 600 to 800 MHz, the resolution of DNP spectra of type III secretion needles (T3SS) could be improved by 22 %, indicating that inhomogeneous broadening is not the dominant effect that limits the resolution of T3SS needles under DNP conditions. The outstanding spectral resolution of this system under DNP conditions can be attributed to its low overall flexibility.

Disruption of Kcc2-dependent inhibition of olfactory bulb output neurons suggests its importance in odour discrimination
Gödde, K., Gschwend(*), O., Puchkov, D., Pfeffer, C. K., Carleton(*), A.; Jentsch, T. J.
Nat Commun, 7:12043
(2016)

Tags: Physiology and Pathology of Ion Transport (Jentsch), Cellular Imaging (Wiesner/Puchkov)

Abstract: Synaptic inhibition in the olfactory bulb (OB), the first relay station of olfactory information, is believed to be important for odour discrimination. We interfered with GABAergic inhibition of mitral and tufted cells (M/T cells), the principal neurons of the OB, by disrupting their potassium-chloride cotransporter 2 (Kcc2). Roughly, 70% of mice died around 3 weeks, but surviving mice appeared normal. In these mice, the resulting increase in the intracellular Cl(-) concentration nearly abolished GABA-induced hyperpolarization of mitral cells (MCs) and unexpectedly increased the number of perisomatic synapses on MCs. In vivo analysis of odorant-induced OB electrical activity revealed increased M/T cell firing rate, altered phasing of action potentials in the breath cycle and disrupted separation of odour-induced M/T cell activity patterns. Mice also demonstrated a severely impaired ability to discriminate chemically similar odorants or odorant mixtures. Our work suggests that precisely tuned GABAergic inhibition onto M/T cells is crucial for M/T cell spike pattern separation needed to distinguish closely similar odours.

The Use of a Combination of RDC and Chiroptical Spectroscopy for Determination of the Absolute Configuration of Fusariumin A from the Fungus Fusarium sp
Liu(*), L. Y., Sun, H., Griesinger(*), C.; Liu(*), J. K.
Natural products and bioprospecting, 6:41-48
(2016)

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: A new alkylpyrrole derivative, fusariumin A (1), was isolated from the culture broth of the fungus Fusarium sp. The absolute configuration of fuasiumin A has been established as (2'R,3'R) using a combination of RDC (residual dipolar coupling)-based NMR and DFT-supported chiroptical spectroscopy. It is worth to note that in this study without the aid of the RDC analysis, an unambiguous determination of configuration and conformation was not feasible due to the excessive conformational possibilities of this open-chain compound.

An Alignment Medium for Measuring Residual Dipolar Couplings in Pure DMSO: Liquid Crystals from Graphene Oxide Grafted with Polymer Brushes
Zong(*), W., Li(*), G. W., Cao(*), J. M., Lei(*), X., Hu(*), M. L., Sun, H., Griesinger(*), C.; Tan(*), R. X.
Angew Chem Int Ed Engl, 55:3690-3693
(2016)

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: Residual dipolar couplings (RDCs) have attracted attention in light of their great impact on the structural elucidation of organic molecules. However, the effectiveness of RDC measurements is limited by the shortage of alignment media compatible with widely used organic solvents, such as DMSO. Herein, we present the first liquid crystal (LC) based alignment medium that is compatible with pure DMSO, thus enabling RDC measurements of polar and intermediate polarity molecules. The liquid crystals were obtained by grafting polymer brushes onto graphene oxide (GO) using free radical polymerization. The resulting new medium offers several advantages, such as absence of background signals, narrow line shapes, and tunable alignment. Importantly, this medium is compatible with pi-conjugated molecules. Moreover, sonication-induced fragmentation can reduce the size of GO sheets. The resulting anisotropic medium has moderate alignment strength, which is a prerequisite for an accurate RDC measurement.

Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist
Bandholtz(*), S., Erdmann(*), S., von Hacht(*), J. L., Exner(*), S., Krause, G., Kleinau(*), G.; Grotzinger(*), C.
Journal of medicinal chemistry, 59:10100-10112
(2016)

Tags: Structural Bioinformatics and Protein Design (Krause, G.)

Abstract: This study investigated the role of individual U-II amino acid positions and side chain characteristics important for U-IIR activation. A complete permutation library of 209 U-II variants was studied in an activity screen that contained single substitution variants of each position with one of the other 19 proteinogenic amino acids. Receptor activation was measured using a cell-based high-throughput fluorescence calcium mobilization assay. We generated the first complete U-II substitution map for U-II receptor activation, resulting in a detailed view into the structural features required for receptor activation, accompanied by complementary information from receptor modeling and ligand docking studies. On the basis of the systematic SAR study of U-II, we created 33 further short and linear U-II variants from eight to three amino acids in length, including d- and other non-natural amino acids. We identified the first high-potency linear U-II analogues. Urolinin, a linear U-II agonist (nWWK-Tyr(3-NO2)-Abu), shows low nanomolar potency as well as improved metabolic stability.

Temperature dependence of cross-effect dynamic nuclear polarization in rotating solids: advantages of elevated temperatures
Geiger, M. A., Orwick-Rydmark, M., Marker, K., Franks, W. T., Akhmetzyanov(*), D., Stöppler, D., Zinke, M., Specker, E., Nazare, M., Diehl, A., van Rossum, B. J., Aussenac(*), F., Prisner(*), T., Akbey, Ü.; Oschkinat, H.
Phys Chem Chem Phys, 18:30696-30704
(2016)

Tags: NMR-Supported Structural Biology (Oschkinat), Medicinal Chemistry (Nazare), Molecular Biophysics (Lange, A.)

Abstract: Dynamic nuclear polarization exploits electron spin polarization to boost signal-to-noise in magic-angle-spinning (MAS) NMR, creating new opportunities in materials science, structural biology, and metabolomics studies. Since protein NMR spectra recorded under DNP conditions can show improved spectral resolution at 180-200 K compared to 110 K, we investigate the effects of AMUPol and various deuterated TOTAPOL isotopologues on sensitivity and spectral resolution at these temperatures, using proline and reproducibly prepared SH3 domain samples. The TOTAPOL deuteration pattern is optimized for protein DNP MAS NMR, and signal-to-noise per unit time measurements demonstrate the high value of TOTAPOL isotopologues for Protein DNP MAS NMR at 180-200 K. The combined effects of enhancement, depolarization, and proton longitudinal relaxation are surprisingly sample-specific. At 200 K, DNP on SH3 domain standard samples yields a 15-fold increase in signal-to-noise over a sample without radicals. 2D and 3D NCACX/NCOCX spectra were recorded at 200 K within 1 and 13 hours, respectively. Decreasing enhancements with increasing 2H-content at the CH2 sites of the TEMPO rings in CD3-TOTAPOL highlight the importance of protons in a sphere of 4-6 A around the nitroxyl group, presumably for polarization pickup from electron spins.

bcTol : a highly water-soluble biradical for efficient dynamic nuclear polarization of biomolecules
Jagtap(*), A. P., Geiger, M. A., Stöppler, D., Orwick-Rydmark, M., Oschkinat, H.; Sigurdsson(*), S. T.
Chem Commun (Camb), 52:7020-7023
(2016)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Dynamic nuclear polarization (DNP) is an efficient method to overcome the inherent low sensitivity of magic-angle spinning (MAS) solid-state NMR. We report a new polarizing agent (), designed for biological applications, that yielded an enhancement value of 244 in a microcrystalline SH3 domain sample at 110 K.

Structural analysis of a signal peptide inside the ribosome tunnel by DNP MAS NMR
Lange, S., Franks, W. T., Rajagopalan(*), N., Döring(*), K., Geiger, M. A., Linden, A., van Rossum, B. J., Kramer(*), G., Bukau(*), B.; Oschkinat, H.
Sci Adv, 2:e1600379
(2016)

Tags: NMR-Supported Structural Biology (Oschkinat), Molecular Biophysics (Lange, A.)

Abstract: Proteins are synthesized in cells by ribosomes and, in parallel, prepared for folding or targeting. While ribosomal protein synthesis is progressing, the nascent chain exposes amino-terminal signal sequences or transmembrane domains that mediate interactions with specific interaction partners, such as the signal recognition particle (SRP), the SecA-adenosine triphosphatase, or the trigger factor. These binding events can set the course for folding in the cytoplasm and translocation across or insertion into membranes. A distinction of the respective pathways depends largely on the hydrophobicity of the recognition sequence. Hydrophobic transmembrane domains stabilize SRP binding, whereas less hydrophobic signal sequences, typical for periplasmic and outer membrane proteins, stimulate SecA binding and disfavor SRP interactions. In this context, the formation of helical structures of signal peptides within the ribosome was considered to be an important factor. We applied dynamic nuclear polarization magic-angle spinning nuclear magnetic resonance to investigate the conformational states of the disulfide oxidoreductase A (DsbA) signal peptide stalled within the exit tunnel of the ribosome. Our results suggest that the nascent chain comprising the DsbA signal sequence adopts an extended structure in the ribosome with only minor populations of helical structure.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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13125 Berlin, Germany
+4930 94793 - 100 
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info(at)fmp-berlin.de

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