Research interests:

Understand the function of large macromolecular complexes involved in transcription and translation by using an integrative structural biology approach.

Transcription and translation are fundamental molecular mechanisms of gene activity regulation with profound implications in human health. The ligand-dependent transcription regulation by nuclear receptors bound to DNA response elements involves the transient assembly of large co-regulator complexes that trigger chromatin remodelling and facilitate the assembly of the general transcription machinery on the promoter of the target gene. Gene expression is also regulated at the level of protein synthesis, for example by protein factors that bind to the ribosome during the translation initiation, elongation and termination phase. The initiation phase is particularly strongly regulated by factors and also by the mRNA itself, and well-characterized reaction intermediates of the initiating ribosomal nano-machinery are potential targets for antibiotics.

The study of large transcription and translation complexes requires an integrative structural biology approach for which we include in particular biochemistry, bio-physics and bio-informatics. We have studied the structure-function relationship of translation termination and most recently several initiation complexes of the bacterial ribosome using cryo-electron microscopy of single molecules, combined with image processing, 3D reconstruction and integration of crystal structures and functional data. We have trapped a 70S ribosome initiation complex with initiation factor IF2 and could reveal the conformational changes of IF2 and of the ribosome occurring upon GTP-hydrolysis. In a recent study we show the important role of mRNA structure in translation initiation regulation. We could reveal the mechanism of transient ribosome-entrapment by an mRNA whose folded state is stabilized by a repressor protein. Importantly, sequence and structure analysis suggests the existence of a conserved site on the ribosome for binding regulatory mRNAs