Nuclear receptor-cofactor interaction

Nuclear receptors (NRs) are multi-domain ligand-modulated transcription factors that act by targeting chromatin-modifying complexes and the transcription machinery to their specific response elements on the DNA. The importance of these NR protein-protein interactions are in contrast to the very limited availability of molecular knowledge on these protein-protein interactions. NRs are validated drug targets as their functioning can be modulated by the type of ligand bound, i.e. via modulation of the protein-protein interactions. The molecular understanding of the influence of the ligand on the structure of the NR, beyond the rather well characterized Ligand Binding Domain (LBD) of the NRs, and on the protein-protein interactions is basically missing.
 
Our research deals with chemical biology approaches to investigate the NR-cofactor interaction. In this our focus is to answer the question how this interaction is regulated on a molecular level. To answer this question we follow several different approaches. We investigate the influence of post-translational modifications on the NR – cofactor binding, and aim to synthesize the NR via protein semi-synthesis. We investigate the cellular localization of NRs and Cofactors under the influence of specific regulating compounds and we design special inhibitors for the NR – cofactor interaction.