RESEARCH REPORT 2009/2010 Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. im Forschungsverbund Berlin e.V. Pharmakologie Leibniz-Institut für Molekulare 2009/2010 REPORT RESEARCH SCIENTIFIC CONTENT ADVISORY BOARD PREFACE What’s New at the FMP? Interview with Acting Director Hartmut Oschkinat....................................................................4 HIGHLIGHTS Propellers, Fibers, and a Magic Angle..................................................................................9 Hiding in the Membrane.......................................................................................................15 Reporters in the Labyrinth....................................................................................................21 Managing the Channels of Perception and the Chemical Workplaces of the Cell..........27 Prof. Dr. Annette G. Beck-Sickinger Leibniz Graduate School of Molecular Biophysics, Berlin...............................................32 Institut für Biochemie Interview with Bernd Reif, Coordinator Universität Leipzig RESEARCH GROUPS Prof. Dr. Bernd Bukau STRUCTURAL BIOLOGY Zentrum für Molekulare Biologie Protein Structure H. Oschkinat.............................................................................................34 Ruprecht-Karls-Universität Heidelberg* Protein Engineering C. Freund............................................................................................38 Structural Bioinformatics and Protein Design G. Krause..................................................42 Prof. Dr. Michael Freissmuth Computational Chemistry/Drug Design R. Kühne.............................................................46 Institut für Pharmakologie Solid-State NMR Spectroscopy B. Reif..............................................................................50 Medizinische Universität Wien Solution NMR P. Schmieder.................................................................................................54 Molecular Imaging – ERC Project Biosensorimaging L. Schröder...................................58 Prof. Dr. Christian Griesinger In-Cell NMR P. Selenko.........................................................................................................62 MPI für Biophysikalische Chemie, Göttingen (Vorsitzender des Beirats) SIGNAL TRANSDUCTION / MOLECULAR GENETICS Physiology and Pathology of Ion Transport T.J. Jentsch................................................. 66 Prof. Dr. Hans-Georg Joost Molecular Cell Physiology I. Blasig..................................................................................... 70 Deutsches Institut für Ernährungsforschung Anchored Signalling E. Klußmann...................................................................................... 74 Potsdam-Rehbrücke Molecular Neuroscience and Biophysics A. Plested.......................................................... 78 Protein Trafficking R. Schülein............................................................................................ 82 Prof. Dr. Gerhard Klebe Biochemical Neurobiology W.E. Siems.............................................................................. 86 Institut für Pharmazeutische Chemie Cellular Imaging B. Wiesner................................................................................................ 90 Universität Marburg CHEMICAL BIOLOGY Chemical Systems Biology R. Frank.....................................................................................94 Prof. Dr. Frauke Melchior Peptide Synthesis M. Beyermann........................................................................................98 Zentrum für Molekulare Biologie Peptide-Lipid-Interactions/Peptide Transport M. Dathe/J. Oehlke................................102 Ruprecht-Karls-Universität Heidelberg Synthetic Organic Biochemistry V. Hagen.........................................................................106 Biophysics of Membrane Proteins S. Keller......................................................................110 Prof. Dr. Eckhard Ottow Mass Spectrometry E. Krause............................................................................................114 Bayer HealthCare Pharmaceuticals Screening Unit J.P. von Kries..............................................................................................118 Berlin Medicinal Chemistry J. Rademann.....................................................................................122 Protein Chemistry D. Schwarzer.........................................................................................126 Prof. Dr. Herbert Waldmann MPI für Molekulare Physiologie Administrative and Technical Services...............................................................................130 Dortmund Index....................................................................................................................................131 Map of the Campus.............................................................................................................134 * Chairperson since 10/2010 Imprint.................................................................................................................................136 2 SCIENTIFIC ADVISORY BOARD CONTENT 3 WHAT‘S NEW AT THE FMP? Prof. Dr. Hartmut Oschkinat Prof. Dr. Hartmut Oschkinat has been the acting What do you consider to be the major accomplishments of the external ones. An example is the recent, very nice collaboration new enzyme targets is too restricted right now. Furthermore, the FMP over the past two years? with Volker Haucke, which produced compounds that inhibit the catalytic centers of enzymes are often highly conserved with quite scientific director of the FMP since January 2009. There has been some very nice work from the group of Thomas formation of “clathrin-coated pits” in the cell membrane. These pits specific structures, making the development of highly specific He is also head of the structural biology department. Jentsch, who has established new disease models. Several years are important for the entry of viruses, other pathogens and disease- inhibitors a difficult task. On the other hand, inhibiting or modu- ago, he had shown that mutations in two isoforms of intracellu- related signals into cells. The discovery has already led to very im- lating highly specific protein-protein interactions within the same In this interview, he outlines major projects and lar CLC chloride/proton exchangers underlie renal endocytosis portant tools for research in cell biology. If more specificity in inhib- protein network might offer a way of developing substances that recent developments at the institute. defects and osteopetrosis, respectively. He has now shown that iting these processes can be achieved, such substances may also modulate specific biological functions. their replacement by a pure Cl- conductance in mice leads to similar point the way to the development of new types of treatments for pathologies, a very unexpected finding that is highly relevant for cell diseases in which endocytosis plays a role. Isn’t there still a problem that occurs when you have an interest- biology. Moreover, by studying the intracellular trafficking of these ing discovery and want to hand it off to industry to take it on for transporters, his team could bring ClC-7 to the cell surface, where it Additionally, the group of Ronald Kühne found a surprising solution further development? How are you coping with this? is now amenable to high throughput screens for ClC-7 inhibitors. As to an old problem. In collaboration with Hans-Günther Schmalz in We have two plans. First, we need to consider the big gap the loss of ClC-7 function causes osteopetrosis, i.e. hypercalcified Cologne, he developed molecules that replace prolines as bind- between scientific results obtained in an academic environment and bones, a pharmacological inhibition of ClC-7 may be useful for ers of important protein interaction domains. These domains bind the proof-of-principle stage at which industry is willing to enter into treating a much more common disease – osteoporosis, undercalci- to proline-rich peptide segments in their interaction partners, re- a project. We will continue to maintain a small translation support fied bones. This research gives us an approach for the development presenting a new class of potential drug targets. The scientists group, which looks at in-house projects and gives a realistic esti- of small molecules to treat a common disease – which is an impor- showed that these compounds are able to block the SH3 domain mate concerning the effort that is necessary to close this gap. This tant aim of the FMP’s activities. of a kinase called Fyn. We hope that the new compounds will help group, called the PEAG, plays an important role in deciding at which us to understand the functions of interactions mediated by proline- point a project should be promoted further either by in-house ef- Another area that has been very fruitful is the development of solid- rich motifs and might open new ways to address so-called “undrug- forts, or be the starting point for a spin-off company, or a pre-GoBio- state NMR methodologies, especially by the group of Bernd Reif. gable” targets. type project, or benefit from the introduction of a biotech or phar- One accomplishment of my own lab, with Barth van Rossum, has maceutical company. been to determine the structure of the alphaB-crystallin oligomer. This field of protein-protein interactions is a major focus of the It’s