The central focus of our research lies in the areas of aptamer- and in vitro selection technologies, chemical genetics, and chemical biology. We currently concentrate on
- Chemical genetics: Aptamer-displacement assays for screening of small molecules inhibitors of target proteins
- Chemical Biology of GEFs
- Synthetic aptamers as biosensors, diagnostics, and therapeutics
We are interested in the functions of guanine nucleotide exchange factors (GEFs), a group of proteins known as activators of small G proteins. Our focus is on several GEFs for ARF, Rac and Rab GTPases. The goal is to find inhibitors which then allow us to characterize the cellular functions of the corresponding GEFs. A successful example of this approach is the cytohesin inhibitor SecinH3. Using this inhibitor we found a novel function of cytohesins as cytoplasmic activators of insulin signaling. Building on these findings a major current focus of the group is to elucidate the molecular mechanism by which cytohesins activate insulin signaling. The general approach in all the cell signaling projects is to integrate chemistry, chemical biology, biochemistry, structural biology and cell biology and to cover a wide spectrum of experimental systems from cell-free assays over cell culture models to in vivo applications. Although we select our targets with respect to their involvement in important physiological and pathophysiological processes, our primary goal is not the development of therapeutics but to use chemical biology to gain insight into fundamental cellular signaling processes.
Hafner, M., Schmitz, A., Grüne, I., Srivatsan, S. G., Paul, B., Kolanus, W., Quast, T., Kremmer, E., Bauer, I., and Famulok, M.
Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance.
Nature 2006, 444, 941-944. [PDF]
An exciting new and rapidly emerging interdisciplinary field of research that merges the life- and engineering sciences is the discipline of Synthetic Biology. To this end, we have recently started to combine our expertise in aptamer research with DNA nanotechnology. Because of DNA’s programmability and structural robustness, DNA rotaxanes with interlocked yet free to move parts are an exciting new approach that promises to open a new field that conjoins the areas of DNA nanotechnology and of interlocked molecular architectures, which will greatly impact synthetic biology and nanorobotics.
Ackermann, D., and Famulok, M.
Pseudo-complementary PNA actuators as reversible switches in dynamic DNA nanotechnology.
Nucleic Acids Res. 2013, 41, 4729-4739. [PDF]
Lohmann, F., Ackermann, D., and Famulok, M.
A reversible light switch for macrocycle mobility in a DNA rotaxane.
J. Am. Chem. Soc. 2012, 134, 11884-11887. [PDF]
Ackermann, D., Jester, S. S., and Famulok, M.
Design strategy for DNA rotaxanes with a mechanically reinforced PX100 axle.
Angew. Chem. Int. Ed. 2012, 51, 6771-6775.
Ackermann, D., Schmidt, T. L., Hannam, J. S., Purohit, C. S., Heckel, A., and Famulok, M.
A double-stranded DNA rotaxane.
Nat. Nanotechnol. 2010, 5, 436-442. [PDF]
Jäger, S., Rasched, G., Kornreich-Leshem, H., Engesser, M., Thum, O., and Famulok, M.
A versatile toolbox for variable DNA functionalisation at high density.
J. Am. Chem. Soc. 2005, 127, 15071-15082. [PDF]
Thum, O., Jäger, S., and Famulok, M.
Functionalized DNA: A new replicable biopolymer.
Angew. Chem. Int. Ed. 2001, 40, 3990-3993. [PDF]
Chemical Genetics: Aptamer-displacement assays for screening of small molecules inhibitors of target proteins
We have established high-throughput cmpatible screening assays that allow converting the inhibitory profile of an aptamer into drug-like inhibitors. We have used these approaches to identify small organic molecules from compound collections (currently > 12,500) that displace an aptamer-protein interaction specifically, and adopt the aptamer’s modulatory properties. Similarly, we can use allosteric, aptamer-regulated ribozymes for the same purpose. These approaches provide access to all-purpose, target-independent assay systems for the identification of small molecules. We apply these compounds in various cellular systems and in model organisms (Drosophila, mouse) for the functional elucidation of target proteins. For example, to elucidate the effect of a compound in certain signalling pathways, we collaborate in analyzing compound activities by genome-wide transcriptional profiling using DNA array technology. We continuously expand our screening platform, consisting of pipetting robots, diverse fluorescence-readers, our collection of drug-like compounds, because we aim to further increase applications of these chemical genetics approaches in our research in the future.
Yamazaki, S., Tan, L., Mayer, G., Hartig, J. S., Song, J.-N., Reuter, S., Restle, T., Laufer, S. D., Grohmann, D., Kräusslich, H.-G., Bajorath, J., and Famulok, M.
Aptamer displacement identifies alternative small-molecule target sites that escape viral resistance.
Chem. Biol. 2007, 14, 804-812. [PDF]
Hartig, J. S., Najafi-Shoushtari, H., Grüne, I., Yan, A., Ellington, A. D., and Famulok, M.
Protein-dependent ribozymes report molecular interactions in real time.
Nat. Biotechnol. 2002, 20, 717-722. [PDF]
Synthetic aptamers as biosensors, diagnostics, and therapeutics
The aim of this research topic is to explore novel prospects for the development of diagnostics, biosensors or molecules of therapeutic interest, based on aptamers.
Gronewold, T. M. A., Baumgartner, A., Hierer, J., Huber, C., Blind, M., Schäfer, F., Blümer, J., Tillmann, T., Kiwitz, A., Zabe-Kühn, M., Quandt, E., and Famulok, M.
Kinetic binding analysis of aptamers targeting HIV-1 proteins by a combination of a microbalance array and mass spectrometry (MAMS).
J. Proteome Res. 2009, 8, 3568-3577. [PDF]
Gronewold, T., Baumgartner, A., Quandt, E., and Famulok, M.
Discrimination of single mutations in cancer-related gene fragments with a surface acoustic wave sensor.
Anal. Chem. 2006, 78, 4865-4871. [PDF]
Gronewold, T. M. A., Glass, S., Quandt, E., and Famulok, M.
Monitoring complex formation in the blood coagulation cascade using aptamer-coated SAW sensors.
BioSens. Bioelectron. 2005, 20, 2044-2052. [PDF]