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Ottmann C.,Chemical Genomics Center | Van Der Hoorn R.A.L.,Max Planck Institute for Plant Breeding Research | Kaiser M.,University of Duisburg - Essen
Chemical Society Reviews | Year: 2012

The pharmaceutical industry is reliant on a constant supply of new chemical entities and molecular targets for disease intervention. In this tutorial review, we want to illustrate that basic research studies on the biological function of natural products involved in plant-pathogen interactions can serve as an inspiring source for the identification of new bioactive entities as well as of strategies on how to achieve small molecule manipulation of biological systems. An application of findings from plant-pathogen interaction studies might therefore display a significant impact on drug discovery. © 2012 The Royal Society of Chemistry.

Toth R.,Max Planck Institute for Plant Breeding Research | Gerding-Reimers C.,Max Planck Institute of Molecular Physiology | Deeks M.J.,Durham University | Menninger S.,Max Planck Institute of Molecular Physiology | And 8 more authors.
Plant Journal | Year: 2012

Chemical modulators are powerful tools to investigate biological processes. To identify circadian clock effectors, we screened a natural product library in the model plant Arabidopsis thaliana. Two compounds, prieurianin (Pri) and prieurianin acetate, were identified as causing a shorter circadian period. Recently, Pri was independently identified as a vesicle trafficking inhibitor and re-named endosidin 1 (ES1). Here we show that Pri primarily affects actin filament flexibility in vivo, later resulting in reduced severing and filament depolymerization. This stabilization of the actin cytoskeleton subsequently causes changes in vesicle trafficking. Pri also affected microfilaments in mammalian cells, indicating that its target is highly conserved; however, it did not alter actin dynamics in vitro, suggesting that its activity requires the presence of actin-associated proteins. Furthermore, well-characterized actin inhibitors shortened the period length of the Arabidopsis clock in a similar way to Pri, supporting the idea that Pri affects rhythms by altering the actin network. We conclude that actin-associated processes influence the circadian system in a light-dependent manner, but their disruption does not abolish rhythmicity. In summary, we propose that the primary effect of Pri is to stabilize the actin cytoskeleton system, thereby affecting endosome trafficking. Pri appears to stabilize actin filaments by a different mechanism from previously described inhibitors, and will be a useful tool to study actin-related cellular processes. © 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.

Vintonyak V.V.,Max Planck Institute of Molecular Physiology | Waldmann H.,Max Planck Institute of Molecular Physiology | Waldmann H.,TU Dortmund | Rauh D.,TU Dortmund | Rauh D.,Chemical Genomics Center
Bioorganic and Medicinal Chemistry | Year: 2011

The site specific functionalization of phosphate groups with amino acid side chains of substrate proteins represents one of the most important regulatory mechanisms of biological systems. Phosphorylation and dephosphorylation are reversibly catalyzed by protein kinases and protein phosphatases, and the aberrant regulation of these enzymes is associated with the onset and progression of various disease states such as cancer, diabetes, neurodegenerative and autoimmune disorders, making these proteins attractive targets for drug discovery. Here we report on strategies currently explored for the identification and development of various inhibitors directed against clinically relevant phosphatases. While over the last years, inhibition of phosphorylation has evolved into a key strategy in targeted therapies, the development of clinically relevant phosphatase inhibitors still faces major bottlenecks and is often plagued by limited selectivity and unfavorable pharmacokinetics. The reader will gain a better understanding of the importance of the field and its current limitations. © 2011 Elsevier Ltd. All rights reserved.

Richter A.,Max Planck Institute of Molecular Physiology | Rose R.,Chemical Genomics Center | Hedberg C.,Max Planck Institute of Molecular Physiology | Waldmann H.,Max Planck Institute of Molecular Physiology | And 2 more authors.
Chemistry - A European Journal | Year: 2012

Modulation of protein-protein interactions (PPIs) is a highly demanding, but also a very promising approach in chemical biology and targeted drug discovery. In contrast to inhibiting PPIs with small, chemically tractable molecules, stabilisation of these interactions can only be achieved with complex natural products, like rapamycin, FK506, taxol, forskolin, brefeldin and fusicoccin. Fusicoccin stabilises the activatory complex of the plant H +-ATPase PMA2 and 14-3-3 proteins. Recently, we have shown that the stabilising effect of fusicoccin could be mimicked by a trisubstituted pyrrolinone (pyrrolidone1, 1). Here, we report the synthesis, functional activity and crystal structure of derivatives of 1 that stabilise the 14-3-3-PMA2 complex. With a limited compound collection three modifications that are important for activity enhancement could be determined: 1) conversion of the pyrrolinone scaffold into a pyrazole, 2) introduction of a tetrazole moiety to the phenyl ring that contacts PMA2, and 3) addition of a bromine to the phenyl ring that exclusively contacts the 14-3-3 protein. The crystal structure of a pyrazole derivative of 1 in complex with 14-3-3 and PMA2 revealed that the more rigid core of this molecule positions the stabiliser deeper into the rim of the interface, enlarging especially the contact surface to PMA2. Combination of the aforementioned features gave rise to a molecule (37) that displays a threefold increase in stabilising the 14-3-3-PMA2 complex over 1. Compound 37 and the other active derivatives show no effect on two other important 14-3-3 protein-protein interactions, that is, with CRaf and p53. This is the first study that describes the successful optimisation of a PPI stabiliser identified by screening. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antonchick A.P.,Max Planck Institute Fu Molekulare Physiologie | Antonchick A.P.,TU Dortmund | Gerding-Reimers C.,Max Planck Institute Fu Molekulare Physiologie | Gerding-Reimers C.,TU Dortmund | And 7 more authors.
Nature Chemistry | Year: 2010

In biology-oriented synthesis the underlying scaffold classes of natural products selected in evolution are used to define biologically relevant starting points in chemical structure space for the synthesis of compound collections with focused structural diversity. Here we describe a highly enantioselective synthesis of natural-product-inspired 3,3′ -pyrrolidinyl spirooxindoles-which contain an all-carbon quaternary centre and three tertiary stereocentres. This synthesis takes place by means of an asymmetric Lewis acid-catalysed 1,3-dipolar cycloaddition of an azomethine ylide to a substituted 3-methylene-2-oxindole using 1-3 mol% of a chiral catalyst formed from a N,P-ferrocenyl ligand and CuPF6 (CH3 CN)4. Cellular evaluation has identified a molecule that arrests mitosis, induces multiple microtubule organizing centres and multipolar spindles, causes chromosome congression defects during mitosis and inhibits tubulin regrowth in cells. Our findings support the concept that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry will be a rich source of compounds with diverse bioactivity. © 2010 Macmillan Publishers Limited. All rights reserved.

Truebestein L.,University of Duisburg - Essen | Tennstaedt A.,University of Duisburg - Essen | Monig T.,Chemical Genomics Center | Krojer T.,Research Institute for Molecular Pathology IMP | And 4 more authors.
Nature Structural and Molecular Biology | Year: 2011

Crystal structures of active and inactive conformations of the human serine protease HTRA1 reveal that substrate binding to the active site is sufficient to stimulate proteolytic activity. HTRA1 attaches to liposomes, digests misfolded proteins into defined fragments and undergoes substrate-mediated oligomer conversion. In contrast to those of other serine proteases, the PDZ domain of HTRA1 is dispensable for activation or lipid attachment, indicative of different underlying mechanistic features. © 2011 Nature America, Inc. All rights reserved.

Rose R.,Chemical Genomics Center | Schaller A.,University of Hohenheim | Ottmann C.,Chemical Genomics Center
Plant Signaling and Behavior | Year: 2010

Serine proteases of the subtilase family are present in Archaea, Bacteria and Eukarya. Many more subtilases are found in plants as compared to other organisms, implying adaptive significance for the expansion of the subtilase gene family in plants. Structural data, however, were hitherto available only for non-plant subtilases. We recently solved the first structure of a plant subtilase, SlSBT3 from tomato (Solanum lycopersicum). SlSBT3 is a multidomain enzyme displaying a subtilisin, a Protease-Associated (PA) and a fibronectin (Fn) III-like domain. Two prominent features set SlSBT3 apart from other structurally elucidated subtilases: (i) activation by PA domain-mediated homo-dimerization and (ii) calcium-independent activity and thermostability. To address the question whether these characteristics are unique features of SlSBT3, or else, general properties of plant subtilases, homology models were calculated for representative proteases from tomato and Arabidopsis using the SlSBT3 structure as template. We found the major structural elements required for the stabilization of the subtilisin domain to be conserved among all enzymes analyzed. PA domain-mediated dimerization as an auto-regulatory mechanism of enzyme activation, on the other hand, appears to be operating in only a subset of the analyzed subtilases. © 2010 Landes Bioscience.

Molzan M.,Chemical Genomics Center | Weyand M.,University of Bayreuth | Rose R.,Chemical Genomics Center | Ottmann C.,Chemical Genomics Center
FEBS Journal | Year: 2012

Myeloid leukaemia factor 1 (MLF1) binds to 14-3-3 adapter proteins by a sequence surrounding Ser34 with the functional consequences of this interaction largely unknown. We present here the high-resolution crystal structure of this binding motif [MLF1(29-42)pSer34] in complex with 14-3-3ε and analyse the interaction with isothermal titration calorimetry. Fragment-based ligand discovery employing crystals of the binary 14-3-3ε/MLF1(29-42)pSer34 complex was used to identify a molecule that binds to the interface rim of the two proteins, potentially representing the starting point for the development of a small molecule that stabilizes the MLF1/14-3-3 protein-protein interaction. Such a compound might be used as a chemical biology tool to further analyse the 14-3-3/MLF1 interaction without the use of genetic methods. © 2011 The Authors Journal compilation © 2011 FEBS.

Molzan M.,Chemical Genomics Center | Ottmann C.,Chemical Genomics Center
Journal of Molecular Biology | Year: 2012

C-RAF kinase is a central component of the Ras-RAF-MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase)-ERK (extracellular signal-regulated kinase) pathway, which has been shown to be activated in 30% of human tumors. 14-3-3 proteins inactivate C-RAF by binding to the two N-terminal phosphorylation-dependent binding sites surrounding S233 and S259. 14-3-3 proteins can bind two target sequences located on one polypeptide chain simultaneously, thereby increasing binding affinity compared to single-site binding and possibly allowing regulated 14-3-3 binding through gatekeeper phosphorylation. To date, it was unclear whether 14-3-3 proteins can bind the two N-terminal phosphorylation-dependent binding sites of C-RAF simultaneously. Fluorescence polarization using phosphorylated peptides demonstrated that S233 is the low-affinity and S259 is the high-affinity binding site, while simultaneous engagement of both sites by 14-3-3ζ enhances affinity compared to single-site binding. Determination of a 1:1 stoichiometry for the di-phosphorylated peptide binding to one 14-3-3ζ dimer with isothermal titration calorimetry was supported by the crystal structure of the 14-3-3ζ/C-RAFpS233,pS259 complex. Cellular localization studies validate the significance of these sites for cytoplasmic retention of C-RAF, suggesting an extended mechanism of RAF regulation by 14-3-3 proteins. © 2012 Elsevier Ltd.

Uhlenheuer D.A.,TU Eindhoven | Young J.F.,Chemical Genomics Center | Nguyen H.D.,Chemical Genomics Center | Scheepstra M.,TU Eindhoven | And 2 more authors.
Chemical Communications | Year: 2011

Cucurbit[8]uril is a supramolecular inducer of protein heterodimerization for proteins appended with methylviologen and naphthalene host elements. Two sets of fluorescent protein pairs, which visualize the specific protein assembly process, enabled the interplay of the supramolecular elements with the proteins to be established. © 2011 The Royal Society of Chemistry.

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