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To be able to develop new drugs against diseases, we need to uncover their molecular basis. Therefore it is essential to understand how diseases develop and how the related cellular processes are regulated.
The research group is active in two main areas. First, we aim at describing the structure and the mode of action of ribonucleoprotein (RNP) complexes involved in RNA processing and gene expression regulation. Second, we develop methodologies to support structure-based drug design (SBDD).
To study the structure of RNP complexes, my team uses a multidisciplinary approach combining Nuclear Magnetic Resonance spectroscopy (NMR), biochemical, biophysical and computational methods. Our philosophy is to tackle the structure of high-molecular weight complexes, whose large size impedes a detailed structural description by NMR only, with an array of different complementary methodologies, such as segmental and specific labeling of both proteins and RNAs, small angle scattering (SAS), electron microscopy (EM), Electron Paramagnetic Resonance (EPR), Fluorescence Resonance Energy Transfer (FRET), mutational analysis and biochemical experiments (e.g. cross-link). With our complementary approach it is possible to examine RNP particles in solution, in their native environment, where they preserve both their structure and dynamic properties.
Recently, we investigated the nucleolar multimeric Box C/D RNP complex responsible for the methylation of the 2’-O-position in rRNA and solved the structures of the 390 kDa enzyme in solution using an integrative structure biology approach (Lapinaite et al. Nature 2013). The structure revealed an unsuspected mechanism of sequentially controlled methylation at dual sites of the rRNA, which might have important implications for ribosome biogenesis (Figure 1).
Figure 1. Structure of the RNA-methylating machinery Box C/D RNP loaded with substrates (Nature, 2013).
The second major aim of our research is the development of methodologies to support structure-based drug design (SBDD). The search of new active molecules starts with screening experiments for the identification of possible interaction partners and proceeds to the development of the small molecule leads into efficient drugs, with both high affinity and specificity to the target and good pharmacokinetic properties. At this stage, structural information on the active ligands in complex with the receptor is essential. We are the developers of INPHARMA (Interligand NOEs for PHArmacophore Mapping), a NMR-based methodology designed to access the relative binding mode of pairs of competitive ligands without need of large protein amounts, recombinant material or expensive labeling schemes (Figure 2). Currently, we develop INPHARMA in new directions and apply the method, in collaboration with pharmaceutical industries or scientific institutes, to medically relevant systems.
Figure 2. Schematic representation of the principle of the INPHARMA NOEs.