Leibniz Research Institute for Molecular Pharmacology

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Leibniz Research Institute for Molecular Pharmacology
Leibniz Research Institute for Molecular Pharmacology
Building of the Leibniz Research Institute for Molecular Pharmacology in Berlin-Buch
Category: research Institute
Carrier: Research Association Berlin
Legal form of the carrier: Registered association
Seat of the wearer: Berlin
Membership: Leibniz Association
Facility location: Berlin book
Type of research: Basic research
Subjects: Natural sciences
Areas of expertise: Life sciences
Basic funding: 16.2 million euros (as of 2014) thereof federal government (50%), federal states (50%)
Management: Dorothea Fiedler (Managing Director), Volker Haucke
Employee: 285, 185 of them scientists
Annotation: Third-party funding of 6.3 million euros (as of 2014)
Homepage: www.fmp-berlin.de

The Leibniz Research Institute for Molecular Pharmacology (FMP, after the original name Research Institute for Molecular Pharmacology , from 2006 to May 2017 Leibniz Institute for Molecular Pharmacology) is a research institution supported by the Forschungsverbund Berlin  e. V. (FVB) and is a member of the Leibniz Association . The institute is based in Berlin on the Berlin-Buch campus , its research activities are assigned to basic research in the field of life sciences as well as molecular biology and pharmacology . A close link between chemistry and biology is characteristic of the scientific work at FMP . The institute was founded in 1992 on the recommendation of the Science Council and goes back to the Institute for Active Ingredient Research of the Academy of Sciences of the GDR, which has existed since 1976 (founding director: Peter Oehme ). When the FMP moved to a newly built institute building, the location moved from Berlin-Friedrichsfelde to Berlin-Buch in 2000 .

Research and Development

Scientists at the FMP are researching key biological processes and thus also causes of diseases at the molecular level, for example cancer and aging processes , including osteoporosis and neurodegenerative diseases . One focus here is on the structure , function and interactions of proteins and their targeted influencing. To this end, modern technologies are developed and used, such as the search for active substances using screening methods , NMR techniques and mass spectrometry .

Organizationally, the institute is divided into three areas:

Molecular Physiology and Cell Biology

FMP researchers in the Molecular Physiology and Cell Biology department investigate intracellular transport and ion homeostasis in the endosomal-lysosomal system . Thomas Jentsch and his research group were able to show that the exchange of chloride ions and protons mediated by intracellular chloride channels (ClCs) and not only the chloride transport is essential for the function of endosomes and lysosomes . His working group discovered and characterized a large number of ion channel diseases ('Channelopathies') that affect various tissues, including the central nervous system , kidneys and bones . The Jentsch laboratory identified the long sought-after volume-regulated anion channel VRAC, which is also permeable to organic osmolytes and amino acids such as glutamate and is therefore important for signal transduction .

Together with Jens von Kries and colleagues, Volker Haucke has developed specific inhibitors of the cellular uptake mediated by the protein clathrin , which could be important in combating viral infections caused by HIV or the Crimean-Congo fever virus . Furthermore, the group around Haucke discovered key functions of phosphoinositolipids such as phosphatidylinositol -3,4-bisphosphate in cellular absorption processes. The release or secretion and uptake of substances also play a central role in synaptic impulse transmission in the nervous system. There the group was able to prove that clathrin-mediated cellular uptake processes and the adapter proteins involved are significantly involved in the reuse of synaptic vesicles. Ivan Horak and his colleagues showed that a disruption of interferon expression caused by mutations in the transcription factor ICSBP in mice leads to an increased susceptibility to viral infections and is responsible for defective haematopoiesis, which causes chronic myeloid leukemia in the animals.

Structural biology

Structural biologists at the FMP develop and use NMR-based methods to elucidate comparatively important cellular proteins and their interaction partners in atomic detail. This provides indications of the mechanisms of action of these proteins and how they are influenced by active ingredients . One focus is on the further development of magic angle solid-state NMR spectroscopy for the structure determination of membrane-integrated or membrane- associated proteins, of elements of the cytoskeleton or very large, dynamic protein complexes . The group of Hartmut Oschkinat solved using this method for the first time the structure of oligomers of the heat shock protein alphaB-crystallin, which is synthesized in many cells to reduce stress from extreme temperatures. In addition, the method of dynamic nuclear polarization (DNP) is being further developed, which makes infrequently available proteins accessible for structural elucidation. Adam Lange's group deals with structural investigations of pharmacologically important biological targets , such as bacterial secretion needles and the voltage-dependent anion channel that is involved in programmed cell death. His group determined a high-resolution structure of the type III secretion system of Shigella .

Chemical biology

Chemical biology groups investigate the biological function of cellular target molecules using biochemical approaches. With high throughput screening and the development of molecules into analytical tools, they take the first steps to new pharmacological and medical knowledge. Phenylhydrazonopyrazolone sulfonates (PHPS1) were identified in collaboration with the Max Delbrück Center for Molecular Medicine (MDC) as inhibitors of the oncogenic phosphatase Shp2 , a target molecule in the development of cancer. Volker Hagen's working group developed cyclic nucleotides and voltage-sensitive dyes that can be activated by light (so-called “caged”) , which allow a detailed molecular analysis of signal processing in living animals, for example the influence of chemoattractive substances on the swimming behavior of marine invertebrates . Michael Beyermann's working group was able to use photochemical and click-chemical probes by incorporating unnatural amino acids into the G protein-coupled CRF receptor to elucidate the complex of the receptor and its urocortin peptide ligand. Another focus is post-translational modifications (PTMs) and the synthesis of functional proteins and conjugates . Christian Hackenberger's group synthesized the tau protein linked to Alzheimer's disease in order to influence the pathological aggregation behavior of tau. A newly developed chemoselective Staudinger phosphite reaction enabled both the PEGylation and intracellular stabilization of pro-apoptotic peptides as well as the targeted, site-specific phosphorylation of peptides on lysine residues , which may be of importance for the regulation of gene expression .

Cooperations

The institute maintains cooperative relationships with various national and international universities, non-university research institutions and business. There are particularly close ties to the Berlin universities. Other partners are e.g. B. the Max Delbrück Center for Molecular Medicine (MDC), the European Molecular Biology Laboratory (EMBL) in Heidelberg and Schering AG .

Web links

Commons : Leibniz Research Institute for Molecular Pharmacology  - Collection of Images

Individual evidence

  1. ↑ a b c Leibniz Institute for Molecular Pharmacology - About us ( English ) Accessed August 30, 2011.
  2. ↑ a b Leibniz Institute for Molecular Pharmacology - About us . Retrieved August 30, 2011.
  3. ↑ Novarino, G., Weinert, S., Rickheit, G. & Jentsch, TJ: Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis . In: Science . tape 328 , 2010, p. 1398-1401 .
  4. ↑ Weinert, S., Jabs, S., Supanchart, C., Schweizer, M., Gimber, N., Richter, M., Rademann, J., Stauber, T., Kornak, U. & Jentsch, TJ: Lysosomal pathology and osteopetrosis upon loss of H + -driven lysosomal Cl- accumulation . In: Science . tape 328 , 2010, p. 1401-1403 .
  5. ↑ Voss, FK, Ullrich, F., Munch, J., Lazarow, K., Lutter, D., Mah, N., Andrade-Navarro, MA, von Kries, JP, Stauber, T. & Jentsch, TJ: Identification of LRRC8 Heteromers as an Essential Component of the Volume-Regulated Anion Channel VRAC . In: Science . tape 344 , 2014, p. 634-638 .
  6. ↑ von Kleist, L., Stahlschmidt, W., Bulut, H., Gromova, K., Puchkov, D., Robertson, MJ, MacGregor, KA, Tomilin, N., Pechstein, A., Chau, N., Chircop, M., Sakoff, J., von Kries, JP, Saenger, W., Krausslich, HG, Shupliakov, O., Robinson, PJ, McCluskey, A. & Haucke, V .: Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition . In: Cell . tape 146 , 2011, pp. 471-484 .
  7. ↑ Posor, Y., Eichhorn-Gruenig, M., Puchkov, D., Schoneberg, J., Ullrich, A., Lampe, A., Muller, R., Zarbakhsh, S., Gulluni, F., Hirsch, E., Krauss, M., Schultz, C., Schmoranzer, J., Noe, F. & Haucke, V .: Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate . In: Nature . tape 499 , 2013, p. 233-237 .
  8. ↑ Kononenko, NL, Puchkov, D., Classen, GA, Walter, AM, Pechstein, A., Sawade, L., Kaempf, N., Trimbuch, T., Lorenz, D., Rosenmund, C., Maritzen, T. & Haucke, V .: Clathrin / AP-2 Mediate Synaptic Vesicle Reformation from Endosome-like Vacuoles but Are Not Essential for Membrane Retrieval at Central Synapses . In: Neuron . tape 82 , 2014, p. 981-988 .
  9. ↑ Podufall, J., Tian, ​​R., Knoche, E., Puchkov, D., Walter, AM, Rosa, S., Quentin, C., Vukoja, A., Jung, N., Lampe, A., Wichmann, C., Bohme, M., Depner, H., Zhang, YQ, Schmoranzer, J., Sigrist, SJ & Haucke, V .: A Presynaptic Role for the Cytomatrix Protein GIT in Synaptic Vesicle Recycling . In: Cell Rep . tape 7 , 2014, p. 1417-1425 .
  10. ↑ Holtschke, T., Lohler, J., Kanno, Y., Fehr, T., Giese, N., Rosenbauer, F., Lou, J., Knobeloch, KP, Gabriele, L., Waring, JF, Bachmann , MF, Zinkernagel, RM, Morse, HC, 3rd, Ozato, K. & Horak, I: Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene . In: Cell . tape 87 , 1996, pp. 307-317 .
  11. ↑ Lange, S., Linden, AH, Akbey, U., Franks, WT, Loening, NM, van Rossum, BJ & Oschkinat, H: The effect of biradical concentration on the performance of DNP-MAS-NMR . In: J. Magn. Reson . tape 216 , 2012, p. 209-212 .
  12. ↑ Salnikov, ES, Ouari, O., Koers, E., Sarrouj, H., Franks, T., Rosay, M., Pawsey, S., Reiter, C., Bandara, P., Oschkinat, H., Tordo, P., Engelke, F. & Bechinger, B .: Developing DNP / Solid-State NMR Spectroscopy of Oriented Membranes . In: Appl. Magn. Reson . tape 43 , 2012, p. 91-106 .
  13. ↑ Jehle, S., Rajagopal, P., Bardiaux, B., Markovic, S., Kuhne, R., Stout, JR, Higman, VA, Klevit, RE, van Rossum, BJ & Oschkinat, H .: Solid- state NMR and SAXS studies provide a structural basis for the activation of alphaB-crystallin oligomers . In: Nature Structural & Molecular Biology . tape 17 , 2010, p. 1037-1042 .
  14. ↑ Demers, JP, habenstein, B., Loquet, A., Vasa, SK, Giller, K., Becker, S., Baker, D., Lange, A. & Sgourakis, NG: High-resolution structure of the Shigella type-III secretion needle by solid-state NMR and cryo-electron microscopy . In: Nature Communications . tape 5 , 2014, p. 4976 .
  15. ↑ Hellmuth, K., Grosskopf, S., Lum, CT, Wurtele, M., Roder, N., von Kries, JP, Rosario, M., Rademann, J. & Birchmeier, W .: Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking . In: Proc Natl Acad Sci USA . tape 105 , 2008, p. 7275-7280 .
  16. ↑ Strunker, T., Weyand, I., Bonigk, W., Van, Q., Loogen, A., Brown, JE, Kashikar, N., Hagen, V., Krause, E. & Kaupp, UB: A K + -selective cGMP-gated ion channel controls chemosensation of sperm . In: Nature Cell Biology . tape 8 , 2006, p. 1149-1154 .
  17. ↑ Coin, I., Katritch, V., Sun, T., Xiang, Z., Siu, FY, Beyer, M., Stevens, RC & Wang, L: Genetically Encoded Chemical Probes in Cells Reveal the Binding Path of urocortin -I to CRF Class B GPCR . In: Cell . tape 155 , 2013, p. 1258-1269 .
  18. ↑ Broncel, M., Krause, E., Black, D. & Hackenberger, CP: The Alzheimer's disease related tau protein as a new target for chemical protein engineering . In: Chemistry - A European Journal . tape 18 , 2012, p. 2488-2492 .
  19. ↑ Nischan, N., Chakrabarti, A., Serwa, RA, Bovee-Geurts, PH, Brock, R. & Hackenberger, CP: Stabilization of Peptides for Intracellular Applications by Phosphoramidate-Linked Polyethylene Glycol Chains . In: Angewandte Chemie International Edition . tape 52 , 2013, p. 11920-11924 .
  20. ↑ Bertran-Vicente, J., Serwa, RA, Schumann, M., Schmieder, P., Krause, E. & Hackenberger, CP: Site-specifically phosphorylated lysine peptides . In: Journal of the American Chemical Society . tape 136 , 2014, pp. 13622-13628 .


Coordinates: 52 ° 37 '27 "  N , 13 ° 30' 17.2"  E