Researchers decode structure and function of docking domains in the biosynthesis of peptide natural products
FRANKFURT. Microorganisms often assemble natural products similar to industrial assembly lines. Certain enzymes, non-ribosomal peptide synthetases (NRPS) play a key role in this process. Biotechnologists at Goethe University have now been able to discover how these enzymes interact with each other. This brings them one step closer to their goal of engineering the production of such peptide natural products.
Many important natural products such as antibiotics, immunosuppressants, or cancer drugs are derived from microorganisms. These natural products are often small proteins or peptides which are generated in the cell by NRPS enzymes similar to a modern automobile factory: at each station additional parts are added to the basic structure until finally a completed automobile leaves the factory. With regard to the NRPS, a specific amino acid is incorporated and processed at each station (module), so that in the end peptides emerge that can be linear, cyclic or otherwise modified including unusual amino acids.
If larger peptides are generated by these systems, often several NRPS enzymes – or assembly lines – operate successively. The order in which this happens is determined by docking domains. These are small regions at the end of the assembly lines that fit with the next NRPS enzyme in line like a key in a lock. Although the basic principles of these NRPS interactions have been known for a long time, the structure of the docking domains was unknown until now. The research groups led by Professor Jens Wöhnert form the Institute of Molecular Biosciences and Professor Helge Bode from Molecular Biotechnology at Goethe University have now been able to successfully explain this.
“We were able to determine the structures of individual docking domains and, for the first time, an NRPS docking domain pair as well,” explains Carolin Hacker, who is a PhD student in Jens Wöhnert’s group. “This made it possible to clarify the rules for the interaction of the docking domains and to change them in such a way that new natural products will be generated,” adds Xiaofeng Cai, postdoctoral researcher in Helge Bode’s group.
“We are only at the beginning of our research: We need structures of additional and structurally diverse docking domains so that in the end we can utilise them like building blocks. Our goal is to connect various biosynthesis pathways and create totally new substances” Wöhnert explains. “Nature has been quite inventive in this area, and there are apparently numerous different ways to mediate the interaction of these complexes,” adds Bode.
Research in this area continues in both groups as part of the LOEWE research cluster MegaSyn. The first results on the structures of additional docking domains are quite promising.
Publication: Carolin Hacker, Xiaofeng Cai, Carsten Kegler, Lei Zhao, A. Katharina Weickhmann, Jan Philip Wurm, Helge B. Bode, Jens Wöhnert: Structure-based redesign of docking domain interactions modulates the product spectrum of a rhabdopeptide-synthesizing NRPS, Nature Communications, https://www.nature.com/ncomms/, DOI: 10.1038/s41467-018-06712-1
You can download an image at: www.uni-frankfurt.de/74390329
Caption: 3D structure of an NRPS docking domain pair. The docking domains of NRPS B (green) connects to the fitting docking domain of NRPS C (magenta) via a β-leaflet.
Further information: Professor Jens Wöhnert, Institute for Molecular Biosciences, Faculty 15, Riedberg Campus, Tel. +49 69 798-29785, firstname.lastname@example.org
Professor Helge B. Bode, Molecular Biotechnology, Faculty 15, Riedberg Campus, Tel.: +49 69 798-29557, email@example.com
Barry Eichengreen appointed Visiting Professor for Financial History 2019
FRANKFURT. Barry Eichengreen, University of California, Berkeley, will hold the Visiting Professorship of Financial History at Goethe University Frankfurt’s House of Finance next year. The professorship is endowed by Metzler Bank and Friedrich Flick Förderungsstiftung.
Barry Eichengreen is George C. Pardee and Helen N. Pardee Professor of Economics and Political Science at the University of California, Berkeley. His research focuses on the history and current operation of the international monetary and financial system.
His most recent books include The Populist Temptation: Economic Grievance and Political Reaction in the Modern Era (2018), How Global Currencies Work: Past, Present, and Future with Livia Chitu and Arnaud Mehl (2017), Hall of Mirrors: The Great Depression, the Great Recession, and the Uses – and Misuses – of History (2015), and Exorbitant Privilege: The Rise and Fall of the Dollar and the Future of the International Monetary System (2011) (shortlisted for the Financial Times and Goldman Sachs Business Book of the Year Award in 2011). One of the best known books by Barry Eichengreen is Golden Fetters: The Gold Standard and the Great Depression, 1919–1939 (1992) which argues that a main cause for the world depression of the 1930ies was the structurally flawed and poorly managed international gold standard. In his most widely cited paper (with Tamim Bayoumi in 1993) he argued that the European Union was less suitable as a Single Currency Area than the United States.
Professor Eichengreen was educated at Yale University in New Haven, CT (M.A in Economics, M.Phil. in Economics, M.A. in History and a Ph.D. in Economics) and the University of California, Santa Cruz (B.A. in Economics and Political Science). He is a Research Associate at NBER (National Bureau of Economic Research) and a Research Fellow at CEPR (Centre for Economic Policy Research). He received a doctor honoris causa from the American University in Paris and, in 2010, the Schumpeter Prize from the International Schumpeter Society. Eichengreen has been named one of Foreign Policy Magazine's 100 Leading Global Thinkers, and he is a past president of the Economic History Association (2010-11 academic year).
During his stay in Frankfurt in May 2019, Barry Eichengreen will head a workshop for young scholars on the occasion of the 50th anniversary of the IBF (Institut für Bank- und Finanzgeschichte) on “Financial History – Reflections on the Past to Tackle Today’s Key Finance Questions” and deliver the keynote address in an international research conference at Goethe University. He will also give a seminar titled “Topics in Macroeconomic History” in the Ph.D. program of the University’s Graduate School GSEFM at the House of Finance.
Professor Eichengreen is the fifth holder of the Goethe University Visiting Professorship of Financial History. In the context of this professorship, distinguished international experts in banking and financial history are invited to share their research insights and methods with researchers, students and the interested public in Frankfurt. Cooperation partners are the Research Center SAFE at the House of Finance and the Institut für Bank- und Finanzgeschichte. Previous Visiting Professors were Benjamin Friedman, Harvard University (2015), Caroline Fohlin, Emory University, Atlanta (2016), Hans-Joachim Voth, University of Zurich (2017) and Harold James, Princeton University (2018). The Visiting Professorship was initially endowed by Metzler Bank and Edmond de Rothschild Group in 2014 on the occasion of Goethe University’s centennial. Since 2018 it is sponsored by Metzler Bank and Friedrich Flick Förderungsstiftung.
Picture material may be downloaded at: http://www.muk.uni-frankfurt.de/74041865?
Further Information: Dr. Stephanie Collet, Research Center SAFE, House of Finance, Campus Westend, Tel. +49 69 798-30041, firstname.lastname@example.org
Excellence strategy: Joint project between Justus-Liebig-University, Goethe University and Max-Planck-Institute clears the last hurdle
FRANKFURT/GIESSEN. With their joint application for an excellence cluster, Goethe University Frankfurt and Justus-Liebig-University Giessen asserted themselves successfully against strong competition. The German Research Foundation announced on 27th September, that the “Cardiopulmonary Institute” (CPI) application, along with 56 other Excellence Cluster projects nationwide, will receive funding for the next seven years.
University President Professor Birgitta Wolff says: “Congratulations to our colleagues in Frankfurt, Giessen and Bad Nauheim, who fought with great success for their scientific ideas and concepts with an excellent application amid a field of strong competitors. The culture of cooperation that has emerged over the course of nearly twelve years among the partners was undoubtedly a decisive moment for this achievement. The formal foundation as an interuniversity institute is new, as is a more developed substantive approach. This latest achievement demonstrates that the effort and investment put into university cardiovascular research paid off.”
Professor Stefanie Dimmeler, lead scientist for Goethe University, emphasizes: “We are thrilled about this huge success which would not have been possible without the support of our great team. The funding of the ‘Cardiopulmonary Institute’ will allow us to create a centre that is unique worldwide with the goal of better understanding heart and lung diseases and identifying new therapeutic options.”
Heart and lung diseases are among the most frequent causes of death worldwide, with multiple interactions between the two organs and challenges in treatment that have yet to be resolved. A coherent understanding of the molecular biology of the individual and cooperative cellular processes, which constitute the foundation of these organs’ homeostasis and their failure in the course of disease, is lacking along with the knowledge of how these processes could be used for new, individualized therapy concepts.
The consortium of the three partners consisting of basic and medical scientists and clinicians has already made fundamental contributions to cardiovascular research and therapeutic developments within the framework of the previously funded Excellence Cluster Cardio-Pulmonary System (ECCPS). The newly approved institute pursues new structural and programmatic paths with the vision of precision biology being the motor for precision medicine. This success is simultaneously an important signal for the sustained development of research strategy at Goethe University.
The joint institute is an interuniversity facility in accordance with §47 of the Hessen Higher Education Act. Within a short time, several new professorships and junior research groups will be set up to further strengthen work in future fields of cardio-vascular research. The CPI will finance cutting edge technologies and flexible innovation programs. The CPI Academy supports research-oriented teaching and promotes academic career development, such as a “science track” for medical students, support of MD and PhD programmes, the financing of career programmes for basic, medical and clinical researchers, and a mentoring programme.
With the new Excellence Cluster, the three partners also strengthen the scientific profile of the region, further enhancing its status in the area of cutting-edge medical research.
Cardiovascular Researcher Dr. Nuno Guimarães Camboa founds a junior research group at Goethe University with €1.25m
FRANKFURT. Following ten years at the renowned University of California San Diego (UCSD), cardiovascular researcher Dr. Nuno Guimarães Camboa is coming to Goethe University. He was lured by the DZHK (German Centre of Cardiovascular Research), which has 28 locations in Germany, one of which is Goethe University. The native Portuguese has been awarded a DZHK junior research group grant and will receive € 1.25m in the next five years to create a research group dedicated to basic research on cardiovascular diseases.
A transcription factor is at the centre of Dr. Nuno Guimarães Camboa’s work. This is a protein which supports the copying of the DNA of the genetic code, “translating” it to RNA. From his previous research projects at the University of California, the junior researcher knows that a specific transcription factor, TBX18, is typically present in three cell types: smooth muscle cells that are found in vessel walls, pacemaker cells in the sino-atrial node (the structure responsible for setting the rhythm of cardiac contraction), and activated connective tissue cells in the injured heart. All three cell types are involved in dangerous cardiovascular diseases: dilations of the aorta (aortic aneurysms), cardiac arrhythmias and morbid proliferation of connective tissue in the heart (cardiac fibrosis).
“We believe that TBX18 affects these cells’ functions”, says Guimarães Camboa. “This factor could therefore play a role in certain cardiovascular diseases.” With his DZHK junior research group at the Goethe University Frankfurt, he wants to investigate which genes are regulated by the transcription factor. The biologist is also planning the targeted inactivation of TBX18 in the relevant cell types. The consequences of this inactivation on the function of the cells will subsequently be closely analysed. “We thus want to better understand the signalling networks active in specific types of cardiovascular disease and hope to thereby improve their early detection and treatment”, explains Guimarães Camboa.
Guimarães Camboa is coming to the DZHK partner site at Goethe University after ten years in the US. He both completed his doctorate and carried out a four-year PostDoc at the University of California. He previously concentrated on the heart’s formation during embryonic development.
With the junior research groups, the DZHK wants to attract talented and qualified young scientists from Germany and abroad, and provide them with scientific independence early on. In addition to leading a research group, the young scientists also have teaching duties, so that they can qualify for a professorship.
Further information: Dr. Nuno Guimarães Camboa, Institute for Cardiovascular Regeneration, University Hospital Frankfurt, email@example.com .
Image may be downloaded at: www.uni-frankfurt.de/73850305
The second generation of an extremely energy-efficient supercomputer model is currently being developed at Goethe University
FRANKFURT. A new supercomputer, on course to set new standards in the field of green IT, is currently being developed at Goethe University under the leadership of Professor Volker Lindenstruth (professorship for supercomputer architecture). The tremendously energy-efficient computer, whose development costs are comparatively low, is based on a large number of high-performing, interconnected graphic cards, and a cooling system that utilizes river water from the Main. The water cooling system lowers the primary energy use for cooling to just about 8 %. Other computing centres require six to ten times this amount of energy for cooling. In 2014, a supercomputer built according to the Lindenstruth’s construction principle achieved the number one slot in the world ranking of energy-efficient supercomputers.
The new GOETHE supercomputer in the Industrial Park Höchst, which is to be realized according to a construction principle further optimized yet similar to its predecessor, will be constructed in two phases. The first construction phase will be concluded by 13th December 2018 and cost approximately € 4.5m. The total costs amounting to € 7.5m will be financed by 50% from federal funds and by 50% from Goethe University and FIAS funds.
The result will be a supercomputer with 18,880 highly interconnected computing cores at its first stage. This translates into a tripling of the computing performance of the preceding model, the LOEWE-CSC, which also began operation in the Industrial Park Hoechst at the end of November 2010. At the time, it was the most energy-efficient supercomputer in Europe according to the international ranking “Green 500”.
On Monday in Frankfurt, Hessen Minister of Higher Education, Research and the Arts, Boris Rhein said: “The GOETHE supercomputer is crucial in order to realize research projects in the natural sciences, medicine, life sciences and economics. … With the approved funding, Goethe University will receive € 3.75m for half of the total costs of € 7.5m. This is an impressive achievement. The state of Hessen supported Goethe University’s application, because high performing computing capacities are essential for Hessen as science location.”
Professor Simone Fulda, Vice President for Research and Academic Infrastructure at Goethe University, states: “Goethe University began the realization of its own high-performance computer centre with significant financial effort many years ago, which was finally able to be built in the Industrial Park Hoechst. It was our good fortune to gain a specialist for supercomputers at Goethe University in the person of Volker Lindenstruth. He developed his own, extraordinarily efficient computer model that is setting standards in this area today and is in demand worldwide. The new Goethe supercomputer clearly continues this development line into the future. We look forward to presenting the completed first construction phase of our new supercomputer to the public on 13th December on location at the Industrial Park Hoechst.”
Professor Volker Lindenstruth, architect of the “Goethe Supercomputer“ emphasises: “The new Goethe supercomputer represents the fulfilment of a vision. High-performance computing is normally extremely expensive and energy-intensive. Thanks to our particularly efficient construction principle, we were able to decrease energy and operation costs to a minimum. This is particularly good news for increasingly IT-intensive science: we can provide maximum computing performance at costs that only would have been unthinkable just a few years ago.”