FMP Publications

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

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References
Quantitative chemical exchange saturation transfer with hyperpolarized nuclei (qHyper-CEST): sensing xenon-host exchange dynamics and binding affinities by NMR
Kunth, M., Witte, C.; Schröder, L.
J Chem Phys, 141:194202
(2014)

Tags: Molecular Imaging (Schröder)

Abstract: The reversible binding of xenon to host molecules has found numerous applications in nuclear magnetic resonance studies. Quantitative characterization of the Xe exchange dynamics is important to understand and optimize the physico-chemical behavior of such Xe hosts, but is often challenging to achieve at low host concentrations. We have investigated a sensitive quantification technique based on chemical exchange saturation transfer with hyperpolarized nuclei, qHyper-CEST. Using simulated signals we demonstrated that qHyper-CEST yielded accurate and precise results and was robust in the presence of large amounts of noise (10%). This is of particular importance for samples with completely unknown exchange rates. Using these findings we experimentally determined the following exchange parameters for the Xe host cryptophane-A monoacid in dimethyl sulfoxide in one type of experiment: the ratio of bound and free Xe, the Xe exchange rate, the resonance frequencies of free and bound Xe, the Xe host occupancy, and the Xe binding constant. Taken together, qHyper-CEST facilitates sensitive quantification of the Xe exchange dynamics and binding to hydrophobic cavities and has the potential to analyze many different host systems or binding sites. This makes qHyper-CEST an indispensable tool for the efficient design of highly specific biosensors.

Development of 1,8-naphthalimides as clathrin inhibitors
MacGregor(*), K. A., Robertson(*), M. J., Young(*), K. A., von Kleist(*), L., Stahlschmidt, W., Whiting(*), A., Chau(*), N., Robinson(*), P. J., Haucke, V.; McCluskey(*), A.
Journal of medicinal chemistry, 57:131-143
(2014)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: We reported the first small molecule inhibitors of the interaction between the clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., clathrin inhibition1). Initial screening of a approximately 17 000 small molecule ChemBioNet library identified 1. Screening of an existing in-house propriety library identified four substituted 1,8-napthalimides as approximately 80-120 muM clathrin inhibitors. Focused library development gave 3-sulfo-N-(4-aminobenzyl)-1,8-naphthalimide, potassium salt (18, IC50 approximately 18 muM). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC50 values of 22, 16, 15, and 15 muM respectively) with a further four (24, 25, 32, 33) more active than 18 with IC50 values of 10, 6.9, 12, and 10 muM, respectively. Docking studies rationalized the structure-activity relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, potassium salt (25) with an IC50 approximately 6.9 muM, is the most potent clathrin terminal domain-amphiphysin inhibitor reported to date.

EU-OPENSCREEN-chemical tools for the study of plant biology and resistance mechanisms
Meiners, T., Stechmann, B.; Frank, R.
J Chem Biol, 7:113-118
(2014)

Tags: Chemical Systems Biology (Frank)

Abstract: EU-OPENSCREEN is an academic research infrastructure initiative in Europe for enabling researchers in all life sciences to take advantage of chemical biology approaches to their projects. In a collaborative effort of national networks in 16 European countries, EU-OPENSCREEN will develop novel chemical compounds with external users to address questions in, among other fields, systems and network biology (directed and selective perturbation of signalling pathways), structural biology (compound-target interactions at atomic resolution), pharmacology (early drug discovery and toxicology) and plant biology (response of wild or crop plants to environmental and agricultural substances). EU-OPENSCREEN supports all stages of a tool development project, including assay adaptation, high-throughput screening and chemical optimisation of the 'hit' compounds. All tool compounds and data will be made available to the scientific community. EU-OPENSCREEN integrates high-capacity screening platforms throughout Europe, which share a rationally selected compound collection comprising up to 300,000 (commercial and proprietary compounds collected from European chemists). By testing systematically this chemical collection in hundreds of assays originating from very different biological themes, the screening process generates enormous amounts of information about the biological activities of the substances and thereby steadily enriches our understanding of how and where they act.

Bioinorganic chemistry of synucleinopathies: deciphering the binding features of Met motifs and His-50 in AS-Cu(I) interactions
Miotto(*), M. C., Binolfi, A., Zweckstetter(*), M., Griesinger(*), C.; Fernandez(*), C. O.
J Inorg Biochem, 141:208-211
(2014)

Tags: In-Cell NMR (Selenko)

Abstract: The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. This process is selectively enhanced by copper in vitro and the interaction is proposed to play a potential role in vivo. Presently, the identity of the Cu(I) binding sites in AS and their relative affinities are under debate. In this work we have addressed unresolved details related to the structural binding specificity and affinity of Cu(I) to full-length AS. We demonstrated conclusively that: (i) the binding preferences of Cu(I) for the Met-binding sites at the N- (Kd=20 muM) and C-terminus (Kd=270 muM) of AS are widely different: (ii) the imidazole ring of His-50 acts as an effective anchoring residue (Kd=50 muM) for Cu(I) binding to AS; and (iii) no major structural rearrangements occur in the protein upon Cu(I) binding. Overall, our work shows that Cu(I) binding to the N- and C-terminal regions of AS are two independent events, with substantial differences in their affinities, and suggest that protein oxidative damage derived from a misbalance in cellular copper homeostasis would target preferentially the N-terminal region of AS. This knowledge is key to understanding the structural-aggregation basis of the copper catalyzed oxidation of AS.

Site-Specific Copper-Catalyzed Oxidation of alpha-Synuclein: Tightening the Link between Metal Binding and Protein Oxidative Damage in Parkinson's Disease
Miotto(*), M. C., Rodriguez(*), E. E., Valiente-Gabioud(*), A. A., Torres-Monserrat(*), V., Binolfi, A., Quintanar(*), L., Zweckstetter(*), M., Griesinger(*), C.; Fernandez(*), C. O.
Inorg Chem, 53:4350-4358
(2014)

Tags: In-Cell NMR (Selenko)

Abstract: Amyloid aggregation of a-synuclein (AS) has been linked to the pathological effects associated with Parkinson's disease (PD). Cu-II binds specifically at the N-terminus of AS and triggers its aggregation. Site-specific Cu-I-catalyzed oxidation of AS has been proposed as a plausible mechanism for metal-enhanced AS amyloid formation. In this study, Cu-I binding to AS was probed by NMR spectroscopy, in combination with synthetic peptide models, site-directed mutagenesis, and C-terminal-truncated protein variants. Our results demonstrate that both Met residues in the motif (MDVFM5)-M-1 constitute key structural determinants for the high-affinity binding of Cu-I to the N-terminal region of AS. The replacement of one Met residue by Ile causes a dramatic decrease in the binding affinity for Cu-I, whereas the removal of both Met residues results in a complete lack of binding. Moreover, these Met residues can be oxidized rapidly after air exposure of the AS-Cu-I complex, whereas Met-116 and Met-127 in the C-terminal region remain unaffected. Met-1 displays higher susceptibility to oxidative damage compared to Met-5 because it is directly involved in both Cu-II and Cu-I coordination, resulting in closer exposure to the reactive oxygen species that may be generated by the redox cycling of copper. Our findings support a mechanism where the interaction of AS with copper ions leads to site-specific metal-catalyzed oxidation in the protein under physiologically relevant conditions. In light of recent biological findings, these results support a role for AS-copper interactions in neurodegeneration in PD.

AhR sensing of bacterial pigments regulates antibacterial defence
Moura-Alves(*), P., Fae(*), K., Houthuys(*), E., Dorhoi(*), A., Kreuchwig, A., Furkert, J., Barison(*), N., Diehl, A., Munder(*), A., Constant, P., Skrahina(*), T., Guhlich-Bornhof(*), U., Klemm(*), M., Koehler(*), A. B., Bandermann(*), S., Goosmann(*), C., Mollenkopf(*), H. J., Hurwitz(*), R., Brinkmann(*), V., Fillatreau(*), S., Daffe(*), M., Tummler, B., Kolbe(*), M., Oschkinat, H., Krause, G.; Kaufmann(*), S. H.
Nature, 512:387-392
(2014)

Tags: Structural Bioinformatics and Protein Design (Krause, G.), NMR-Supported Structural Biology (Oschkinat), Protein Trafficking (Schülein)

Abstract: The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns.

Controlled thioamide vs. amide formation in the thioacid-azide reaction under acidic aqueous conditions
Mühlberg, M., Siebertz, K. D., Schlegel, B., Schmieder, P.; Hackenberger, C. P.
Chem Commun (Camb), 50:4603-4606
(2014)

Tags: Solution NMR (Schmieder), Chemical Biology II (Hackenberger)

Abstract: The thioacid-azide reaction and its chemoselectivity were probed with alkyl azides for a potential application to form amide bonds in aqueous solvents. Our results reveal that under acidic conditions thioamides were formed as major reaction products suggesting a competing mechanism, whereas reactions forming amides predominated at slightly higher pH values.

Interferon-gamma safeguards blood-brain barrier during experimental autoimmune encephalomyelitis
Ni(*), C., Wang(*), C., Zhang(*), J., Qu(*), L., Liu(*), X., Lu(*), Y., Yang(*), W., Deng(*), J., Lorenz, D., Gao(*), P., Meng(*), Q., Yan(*), X., Blasig, I. E.; Qin(*), Z.
The American journal of pathology, 184:3308-3320
(2014)

Tags: Molecular Cell Physiology (Blasig, I.E.), Cellular Imaging (Wiesner)

Abstract: The function of blood-brain barrier is often disrupted during the progression of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the molecular mechanism of blood-brain barrier modulation during neuroinflammation remains unclear. Herein, we show that the expression of interferon-gamma (IFNgamma) receptor on endothelial cells (ECs) protected mice from the brain inflammation during EAE. IFNgamma stabilized the integrity of the cerebral endothelium and prevented the infiltration of leukocytes into the brain. Further analysis revealed that IFNgamma increased the expression of tight junction proteins zonula occludens protein 1 and occludin, as well as membranous distribution of claudin-5, in brain ECs. Silencing claudin-5 abolished the IFNgamma-mediated improvement of EC integrity. Taken together, our results show that IFNgamma, a pleiotropic proinflammatory cytokine, stabilizes blood-brain barrier integrity and, therefore, prevents brain inflammation during EAE.

Isolation of Microcystins from the Cyanobacterium Planktothrix rubescens Strain No80
Niedermeyer(*), T. H., Schmieder, P.; Kurmayer(*), R.
Natural products and bioprospecting, 4:37-45
(2014)

Tags: Solution NMR (Schmieder)

Abstract: ABSTRACT: Three minor microcystins have been isolated from a Planktothrix rubescens strain. Their structures have been elucidated by one- and two-dimensional NMR spectroscopy and high-resolution tandem mass spectrometry as the compounds [Asp(3),(E)-Dhb(7)]MC-LY (1), [Asp(3),(E)-Dhb(7)]MC-HtyW (2), and [Asp(3),(E)-Dhb(7)]MC-LW (3). The amino acids found at the variable positions 2 and 4 of the microcystin core structure are in accordance with the predicted amino acid substrate activation selectivities of the non-ribosomal peptide synthetases McyA and McyB described earlier for this strain. All structural microcystin variants produced by this strain were shown to inhibit protein phosphatase 1 in the nanomolar range.

Site-specific PEGylation of proteins: recent developments
Nischan, N.; Hackenberger, C. P.
J Org Chem, 79:10727-10733
(2014)

Tags: Chemical Biology II (Hackenberger)

Abstract: The attachment of linear polyethylene glycol (PEG) to peptides and proteins for their stabilization for in vivo applications is a milestone in pharmaceutical research and protein-drug development. However, conventional methods often lead to heterogeneous PEGylation mixtures with reduced protein activity. Current synthetic efforts aim to provide site-specific approaches by chemoselective targeting of canonical and noncanonical amino acids and to improve the PEG architecture. This synopsis highlights recent work in this area, which also resulted in improved pharmacokinetics of peptide and protein therapeutics.

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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
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info(at)fmp-berlin.de

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