Previous and current research

We study the structure and dynamics of biomolecular complexes and catalytic RNAs in solution by nuclear magnetic resonance (NMR) spectroscopy in combination with a wide range of biochemical and biophysical techniques. Recent advances in the NMR methodology and instrumentation have allowed overcoming traditional size limitations and have made NMR a very powerful technique, in particular for the investigation of highly dynamic, partially inhomogeneous molecules and complexes.

The laboratory focuses on studying: 1) The interaction of small drugs with cellular receptors; and 2) Structure-activity and dynamics-activity relationship of RNP complexes and catalytic RNAs involved in RNA processing.

Conformational switches occur in macromolecular receptors at all cellular levels in dependence of the presence of small organic molecules, which are able to trigger or inhibit specific cellular processes.We develop both computational and experimental tools to access the structure of large receptors in complex with function regulators. In particular we study the functional mechanisms of anti-cancer drug-leads, designed as inhibitors of kinases, proteasome and tubulin.

A second aim of our work is to describe the features of RNA-protein recognition in RNP complex enzymes and to characterise the structural basis for their function. Recently, we have determined the three-dimensional architecture of the ternary complex between the 15.5 kDa protein/U4 RNA and the hPrp31 protein, which is a constituent of the U4/U6 particle in the spliceosome (in collaboration with M.Wahl and R. Lührmann at the MPI, Göttingen; see figure). Currently, we are investigating the nucleolar multimeric box C/D RNP complex responsible for the methylation of the 2’-OH position in rRNA. 2’-O-methylation is one of the most relevant modifications of newly transcribed RNA as it occurs around functional regions of the ribosome. This suggests that 2’-O-methylation may be necessary for proper folding and structural stabilisation of rRNA in vivo. In another project, we collaborate with the group of Ramesh Pillai (page 95) at EMBL Grenoble to understand the structure of RNP complexes involved in the regulation of gene expression through small non-coding RNAs.

Future projects and goals

We use NMR spectroscopy to study how proteins and nucleic acids interact with each other and the structural basis for the activity of complex enzymes. In addition we dedicate our efforts to understand the activity of small-molecule inhibitors of cellular targets relevant in anti-cancer therapy.We use innovative NMR techniques to access the structure of large, dynamic multi-component complexes in combination with otherstructural biology techniques (SANS, X-ray and EM) and biochemical data. Our philosophy is to combine high-resolution structures of single-components of the complexes with both structural descriptors of the intermolecular interactions in solution and computational methods, to obtain an accurate picture of the molecular basis of cellular processes.

Chemistry at EMBL