Towards personalized molecular medicine: Structural basis of neurodegenerative diseases and cancer (X)

Detailed knowledge of the three-dimensional (3D) structures of proteins and their complexes is essential to understand their pathophysiological roles, and to develop novel therapeutic compounds (rational drug design). We will exploit our recent structure of the homodimeric androgen receptor ligand binding domain (AR-LBD) as a starting point to develop novel drugs to treat prostate cancer. Further, we will crystallize and resolve the crystal structures of wild-type and mutant AR-LBD bound to agonist and antagonist compounds. We will also characterize the interactome of three nuclear receptors that are essential regulators of neural stem cells, GR, TLX and PNR, and resolve 3D structures of their most relevant complexes. These receptors have been recently associated with the onset and progression of brain tumours and various human neurological disorders and are therefore attractive drug targets. Another major aim of the current proposal is to contribute to the understanding of the aetiology of two important neurodegenerative diseases: Parkinson’s disease and Spinal Muscular Atrophy (SMA). We will solve the 3D crystal structure of the kinase domain of the parkin activator, PINK, both free and bound to substrates, to rationalize on a structural basis the recognition mechanism of its (patho)physiologically relevant substrates, most
notably of ubiquitin and parkin itself. We will continue our structure-and-function studies of the mechanism by which two nuclear splicing factors, hnRNP A1 and Sam68, cooperate to exclude
exon 7 from SMN2 premRNA. This exon-skipping event is critical for the development of SMA in
affected individuals, who lack a functional copy of the “normal” SMN1 gene. We will solve the crystal structures of Sam68-RNA and hnRNP A1-RNA complexes using oligonucleotides that correspond to their binding sites on SMN2 exon 7. Finally, we will solve the structure of the Nterminal,
regulatory domain of human TET2 protein, a key regulator of AR, GR and TLX.