FMP Publications

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

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References
Small-molecule inhibitors of AF6 PDZ-mediated protein-protein interactions
Vargas, C., Radziwill(*), G., Krause, G., Diehl, A., Keller, S., Kamdem, N., Czekelius(*), C., Kreuchwig, A., Schmieder, P., Doyle(*), D., Moelling(*), K., Hagen, V., Schade(*), M.; Oschkinat, H.
Chemmedchem, 9:1458-1462
(2014)

Tags: NMR-Supported Structural Biology (Oschkinat), Solution NMR (Schmieder), Synthetic Organic Biochemistry (Hagen), Structural Bioinformatics and Protein Design (Krause, G.), Biophysics of Membrane Proteins (Keller), Synthetic Organic Biochemistry (Hagen)

Abstract: PDZ (PSD-95, Dlg, ZO-1) domains are ubiquitous interaction modules that are involved in many cellular signal transduction pathways. Interference with PDZ-mediated protein-protein interactions has important implications in disease-related signaling processes. For this reason, PDZ domains have gained attention as potential targets for inhibitor design and, in the long run, drug development. Herein we report the development of small molecules to probe the function of the PDZ domain from human AF6 (ALL1-fused gene from chromosome 6), which is an essential component of cell-cell junctions. These compounds bind to AF6 PDZ with substantially higher affinity than the peptide (Ile-Gln-Ser-Val-Glu-Val) derived from its natural ligand, EphB2. In intact cells, the compounds inhibit the AF6-Bcr interaction and interfere with epidermal growth factor (EGF)-dependent signaling.

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.

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.

Site-specifically phosphorylated lysine peptides
Bertran-Vicente, J., Serwa(*), R. A., Schümann, M., Schmieder, P., Krause, E.; Hackenberger, C. P.
J Am Chem Soc, 136:13622-13628
(2014)

Tags: Chemical Biology II (Hackenberger), Mass Spectrometry (Krause, E.), Solution NMR (Schmieder)

Abstract: Protein phosphorylation controls major processes in cells. Although phosphorylation of serine, threonine, and tyrosine and also recently histidine and arginine are well-established, the extent and biological significance of lysine phosphorylation has remained elusive. Research in this area has been particularly limited by the inaccessibility of peptides and proteins that are phosphorylated at specific lysine residues, which are incompatible with solid-phase peptide synthesis (SPPS) due to the intrinsic acid lability of the P( horizontal lineO)-N phosphoramidate bond. To address this issue, we have developed a new synthetic route for the synthesis of site-specifically phospholysine (pLys)-containing peptides by employing the chemoselectivity of the Staudinger-phosphite reaction. Our synthetic approach relies on the SPPS of unprotected epsilon-azido lysine-containing peptides and their subsequent reaction to phosphoramidates with phosphite esters before they are converted into the natural modification via UV irradiation or basic deprotection. With these peptides in hand, we demonstrate that electron-transfer dissociation tandem mass spectrometry can be used for unambiguous assignment of phosphorylated-lysine residues within histone peptides and that these peptides can be detected in cell lysates using a bottom-up proteomic approach. This new tagging method is expected to be an essential tool for evaluating the biological relevance of lysine phosphorylation.

Active and silent chromophore isoforms for phytochrome Pr photoisomerization: An alternative evolutionary strategy to optimize photoreaction quantum yields
Yang, Y., Linke, M., von Haimberger, T., Matute, R., Gonzalez, L., Schmieder, P.; Heyne, K.
Structural dynamics (Melville, N.Y.), 1:014701
(2014)

Tags: Solution NMR (Schmieder)

Abstract: Photoisomerization of a protein bound chromophore is the basis of light sensing of many photoreceptors. We tracked Z-to-E photoisomerization of Cph1 phytochrome chromophore PCB in the Pr form in real-time. Two different phycocyanobilin (PCB) ground state geometries with different ring D orientations have been identified. The pre-twisted and hydrogen bonded PCB(a) geometry exhibits a time constant of 30 ps and a quantum yield of photoproduct formation of 29%, about six times slower and ten times higher than that for the non-hydrogen bonded PCB(b) geometry. This new mechanism of pre-twisting the chromophore by protein-cofactor interaction optimizes yields of slow photoreactions and provides a scaffold for photoreceptor engineering.

Physicochemical properties of cells and their effects on intrinsically disordered proteins (IDPs)
Theillet, F. X., Binolfi, A., Frembgen-Kesner(*), T., Hingorani(*), K., Sarkar(*), M., Kyne(*), C., Li(*), C., Crowley(*), P. B., Gierasch(*), L., Pielak(*), G. J., Elcock(*), A. H., Gershenson(*), A.; Selenko, P.
Chem Rev, 114:6661-6714
(2014)

Tags: In-Cell NMR (Selenko)

Efficient modification of alpha-synuclein serine 129 by protein kinase CK1 requires phosphorylation of tyrosine 125 as a priming event
Kosten, J., Binolfi, A., Stuiver, M., Verzini, S., Theillet, F. X., Bekei, B., van Rossum, M.; Selenko, P.
Acs Chem Neurosci, 5:1203-1208
(2014)

Tags: In-Cell NMR (Selenko)

Abstract: S129-phosphorylated alpha-synuclein (alpha-syn) is abundantly found in Lewy-body inclusions of Parkinson's disease patients. Residues neighboring S129 include the alpha-syn tyrosine phosphorylation sites Y125, Y133, and Y136. Here, we use time-resolved NMR spectroscopy to delineate atomic resolution insights into the modification behaviors of different serine and tyrosine kinases targeting these sites and show that Y125 phosphorylation constitutes a necessary priming event for the efficient modification of S129 by CK1, both in reconstituted kinase reactions and mammalian cell lysates. These results suggest that alpha-syn Y125 phosphorylation augments S129 modification under physiological in vivo conditions.

Live Cell NMR
Freedberg(*), D. I.; Selenko, P.
Annu Rev Biophys, 43:171-192
(2014)

Tags: In-Cell NMR (Selenko)

Abstract: Ever since scientists realized that cells are the basic building blocks of all life, they have been developing tools to look inside them to reveal the architectures and mechanisms that define their biological functions. Whereas "looking into cells" is typically said in reference to optical microscopy, high-resolution in-cell and on-cell nuclear magnetic resonance (NMR) spectroscopy is a powerful method that offers exciting new possibilities for structural and functional studies in and on live cells. In contrast to conventional imaging techniques, in-and on-cell NMR methods do not provide spatial information on cellular biomolecules. Instead, they enable atomic-resolution insights into the native cell states of proteins, nucleic acids, glycans, and lipids. Here we review recent advances and developments in both fields and discuss emerging concepts that have been delineated with these methods.

Disorder and residual helicity alter p53-Mdm2 binding affinity and signaling in cells
Borcherds(*), W., Theillet, F. X., Katzer(*), A., Finzel(*), A., Mishall(*), K. M., Powell(*), A. T., Wu(*), H., Manieri(*), W., Dieterich(*), C., Selenko, P., Loewer(*), A.; Daughdrill(*), G. W.
Nat Chem Biol, 10:1000-1002
(2014)

Tags: In-Cell NMR (Selenko)

Abstract: Levels of residual structure in disordered interaction domains determine in vitro binding affinities, but whether they exert similar roles in cells is not known. Here, we show that increasing residual p53 helicity results in stronger Mdm2 binding, altered p53 dynamics, impaired target gene expression and failure to induce cell cycle arrest upon DNA damage. These results establish that residual structure is an important determinant of signaling fidelity in cells.

The specific monomer/dimer equilibrium of the corticotropin-releasing factor receptor type 1 is established in the endoplasmic reticulum
Teichmann, A., Gibert, A., Lampe, A., Grzesik, P., Rutz, C., Furkert, J., Schmoranzer, J., Krause, G., Wiesner, B.; Schülein, R.
J Biol Chem, 289:24250-24262
(2014)

Tags: Protein Trafficking (Schülein), Cellular Imaging (Wiesner), Structural Bioinformatics and Protein Design (Krause, G.), Molecular Pharmacology and Cell Biology (Haucke)

Abstract: G protein-coupled receptors (GPCRs) represent the most important drug targets. Although the smallest functional unit of a GPCR is a monomer, it became clear in the past decades that the vast majority of the receptors form dimers. Only very recently, however, data were presented that some receptors may in fact be expressed as a mixture of monomers and dimers and that the interaction of the receptor protomers is dynamic. To date, equilibrium measurements were restricted to the plasma membrane due to experimental limitations. We have addressed the question as to where this equilibrium is established for the corticotropin-releasing factor receptor type 1. By developing a novel approach to analyze single molecule fluorescence cross-correlation spectroscopy data for intracellular membrane compartments, we show that the corticotropin-releasing factor receptor type 1 has a specific monomer/dimer equilibrium that is already established in the endoplasmic reticulum (ER). It remains constant at the plasma membrane even following receptor activation. Moreover, we demonstrate for seven additional GPCRs that they are expressed in specific but substantially different monomer/dimer ratios. Although it is well known that proteins may dimerize in the ER in principle, our data show that the ER is also able to establish the specific monomer/dimer ratios of GPCRs, which sheds new light on the functions of this compartment.

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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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