Griesinger's Group @ The MPIBPC
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Liquid-state NMR RNA can assume a wide variety of conformations in the execution of its biological roles. Moreover, its importance as a therapeutic target is widely recognized. These two facts make structural studies of RNA molecules a highly relevant research topic. When not found in complex with proteins, RNA usually exhibits conformational flexibility, a fact that often hampers crystallization. Both the difficulty in obtaining crystals and the interest in the relationship between the dynamic behavior of RNA and its biological function suggest NMR (Nuclear Magnetic Resonance) spectroscopy as an obvious choice for probing the structure and dynamics of RNA molecules in solution. In the past two decades, the apparent monopoly of proteins as biological catalysts has been invalidated by the discovery that several RNA molecules can form active sites that catalyze chemical reactions. Moreover, there is extensive speculation that RNA catalysis might have played a key role in the early stages of evolution. We aim to unravel the mechanism of catalysis of several ribozymes from a structural point of view, namely, to explain the catalytic function of RNA molecules in terms of three-dimensional folding. For this purpose, we work to develop a new NMR methodology to follow selective structural features throughout the catalytic reaction. The systems we investigate are the hammerhead ribozyme and two ribozymes derived from group I and group II introns. Moreover, we explore the interaction of RNA molecules with antibiotics in order to understand the mechanisms that play a role in the specific recognition and inhibition of RNA biological activity. In a second field of research, we aim to contribute to a structure-based drug design by studying the receptor-bound conformation mechanisms of small organic molecules. We recently determined the conformation of the anti-tumor drug epothilone A in complex with tubulin. This structure provides the first piece of experimental information on the active conformation of this class of microtubule stabilizers, and allows explaining a large share of the biological data available on the tubulin polymerization activity of the epothilone derivatives. Currently, we are developing a new combined experimental and theoretical approach for determining the orientation of ligands in the receptor-binding pocket.
Last modification Fri Jan 9 14:56:17 2004 |
