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Design of dual ligands using excessive pharmacophore query alignment (2012)

Daniel Moser Joanna Wisniewska Steffen Hahn Estel la Buscató Franca-Maria Klingler Janosch Achenbach Bettina Hofmann Dieter Steinhilber Ewgenij Proschak

Oral presentation Dual- or multi-target ligands have gained increased attention in the past years due to several advantages, including more simple pharmacokinetic and phamarcodynamic properties compared to a combined application of several drugs. Furthermore multi-target ligands often possess improved efficacy [1]. We present a new approach for the discovery of dual-target ligands using aligned pharmacophore models combined with a shape-based scoring. Starting with two sets of known active compounds for each target, a number of different pharmacophore models is generated and subjected to pairwise graph-based alignment using the Kabsch-Algorithm [2,3]. Since a compound may be able to bind to different targets in different conformations, the algorithm aligns pairs of pharmacophore models sharing the same features which are not necessarily at the exactly same spatial distance. Using the aligned models, a pharmacophore search on a multi-conformation-database is performed to find compounds matching both models. The potentially “dual” ligands are scored by a shape-based comparison with the known active molecules using ShaEP [4]. Using this approach, we performed a prospective fragment-based virtual screening for dual 5-LO/sEH inhibitors. Both enzymes play an important role in the arachidonic acid cascade and are involved in inflammatory processes, pain, cardiovascular diseases and allergic reactions [5,6]. Beside several new selective inhibitors we were able to find a compound inhibiting both enzymes in low micromolar concentrations. The results indicate that the idea of aligned pharmacophore models can be successfully employed for the discovery of dual-target ligands.

Open Access 7th German Conference on Chemoinformatics: 25 CIC-Workshop : Goslar, Germany. 6-8 November 2011 ; meeting abstracts (2012)

IAPs as E3 ligases of Rac1 : shaping the move (2012)

Tripat Kaur Oberoi-Khanuja Krishnaraj Rajalingam

Inhibitors of Apoptosis Proteins (IAPs) are well-studied E3 ubiquitin ligases predominantly known for regulation of apoptosis. We uncovered that IAPs can function as a direct E3 ubiquitin ligase of RhoGTPase Rac1. cIAP1 and XIAP directly conjugate polyubiquitin chains to Lysine 147 of activated Rac1 and target it for proteasomal degradation. Consistently, loss of these IAPs by various strategies led to stabilization of Rac1 and mesenchymal mode of migration in tumor cells. IAPs also regulate Rac1 degradation upon RhoGDI1 depletion and CNF1 toxin treatment. Our observations revealed an evolutionarily conserved role of IAPs in regulating Rac1 stability shedding light on to the mechanisms behind ubiquitination–dependent inactivation of Rac1 signaling.

Study of E. coli Hfq's RNA annealing acceleration and duplex destabilization activities using substrates with different GC-contents (2012)

Martina Doetsch Sabine Stampfl Boris Fürtig Mads Beich-Frandsen Krishna Saxena Meghan Lybecker Renée Schroeder

Folding of RNA molecules into their functional three-dimensional structures is often supported by RNA chaperones, some of which can catalyse the two elementary reactions helix disruption and helix formation. Hfq is one such RNA chaperone, but its strand displacement activity is controversial. Whereas some groups found Hfq to destabilize secondary structures, others did not observe such an activity with their RNA substrates. We studied Hfq’s activities using a set of short RNAs of different thermodynamic stabilities (GC-contents from 4.8% to 61.9%), but constant length. We show that Hfq’s strand displacement as well as its annealing activity are strongly dependent on the substrate’s GC-content. However, this is due to Hfq’s preferred binding of AU-rich sequences and not to the substrate’s thermodynamic stability. Importantly, Hfq catalyses both annealing and strand displacement with comparable rates for different substrates, hinting at RNA strand diffusion and annealing nucleation being rate-limiting for both reactions. Hfq’s strand displacement activity is a result of the thermodynamic destabilization of the RNA through preferred single-strand binding whereas annealing acceleration is independent from Hfq’s thermodynamic influence. Therefore, the two apparently disparate activities annealing acceleration and duplex destabilization are not in energetic conflict with each other.

N-(2,6-Diisopropylphenyl)formamide toluene 0.33-solvate (2012)

Matthias Berger Jan W. Bats Norbert Auner

The crystal packing of the title compound, C13H19NO·0.33C7H8, shows a channel at [001], which contains grossly disordered toluene solvent molecules. The angle between the benzene ring and the mean plane of the formamide group is 71.1 (1)°. The amide groups of neighbouring molecules are connected by N—H(...)O hydrogen bonds, forming 21 helical chains propagating along [001]. Molecules are also connected by weak intermolecular C—H(...)O hydrogen bonds, forming 61 helices.

Direct evidence that the N-terminal extensions of the TAP complex act as autonomous interaction scaffolds for the assembly of the MHC I peptide-loading complex (2012)

Sabine Hulpke Maiko Tomioka Elisabeth Kremmer Kazumitsu Ueda Rupert Abele Robert Tampé

The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD0, which is correctly targeted to and inserted into the ER membrane. In the absence of coreTAP, each TMD0 recruits tapasin in a 1:1 stoichiometry. Although the TMD0s lack known ER retention/retrieval signals, they are localized to the ER membrane even in tapasin-deficient cells. We conclude that the TMD0s of TAP form autonomous interaction hubs linking antigen translocation into the ER with peptide loading onto MHC I, hence ensuring a major function in the integrity of the antigen-processing machinery.

Defining the core proteome of the chloroplast envelope membranes (2013)

Stefan Simm Dimitrios G. Papasotiriou Mohamed Ibrahim Matthias Leisegang Bernd Müller Tobias Schorge Michael Karas Oliver Mirus Maik S. Sommer Enrico Schleiff

High-throughput protein localization studies require multiple strategies. Mass spectrometric analysis of defined cellular fractions is one of the complementary approaches to a diverse array of cell biological methods. In recent years, the protein content of different cellular (sub-)compartments was approached. Despite of all the efforts made, the analysis of membrane fractions remains difficult, in that the dissection of the proteomes of the envelope membranes of chloroplasts or mitochondria is often not reliable because sample purity is not always warranted. Moreover, proteomic studies are often restricted to single (model) species, and therefore limited in respect to differential individual evolution. In this study we analyzed the chloroplast envelope proteomes of different plant species, namely, the individual proteomes of inner and outer envelope (OE) membrane of Pisum sativum and the mixed envelope proteomes of Arabidopsis thaliana and Medicago sativa. The analysis of all three species yielded 341 identified proteins in total, 247 of them being unique. 39 proteins were genuine envelope proteins found in at least two species. Based on this and previous envelope studies we defined the core envelope proteome of chloroplasts. Comparing the general overlap of the available six independent studies (including ours) revealed only a number of 27 envelope proteins. Depending on the stringency of applied selection criteria we found 231 envelope proteins, while less stringent criteria increases this number to 649 putative envelope proteins. Based on the latter we provide a map of the outer and inner envelope core proteome, which includes many yet uncharacterized proteins predicted to be involved in transport, signaling, and response. Furthermore, a foundation for the functional characterization of yet unidentified functions of the inner and OE for further analyses is provided.

Fachspezifischer Anhang zur SPoL (Teil III): Studienfach Chemie im Studiengang L3 (2008)

Habilitationsordnung der Mathematisch–Naturwissenschaftlichen Fachbereiche der Johann Wolfgang Goethe-Universität Frankfurt am Main vom 04.02.1992 (ABl. 1992, S.816 ff.), zuletzt geändert am 28. April 2002 (StAnz. 41/2003, S. 4024 – 4025) : genehmigt durch Beschluss des Präsidiums der Johann Wolfgang Goethe-Universität Frankfurt am Main am 27. Januar 2009 ; hier: Änderung bzw. Ergänzung (2009)

Promotionsordnung der Mathematisch-Naturwissenschaftlichen Fachbereiche der Johann Wolfgang Goethe-Universität in Frankfurt am Main vom 26. Mai 1993 (ABL.1/94, S. 21) zuletzt geändert am 05.09.2007 (Uni-Report 13.11.2008) : genehmigt durch Beschluss des Präsidiums der Johann Wolfgang Goethe-Universität Frankfurt am Main am 27. Januar 2009 ; hier: Änderung (2009)

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