From Genome to Life:

MORAS Dino

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département De Biologie Et De Génomique Structurales, 1, Rue Laurent Fries, Illkirch 67400, France

title: Structural genomics of orphan nuclear receptors

The nuclear receptors (NRs) are ligand dependant transcription factors that regulate the expression of specific target genes. NRs are modular in their structure, the ligand binding domain (LBD) being responsible for a ligand inducible transcriptional activity and representing an important target for pharmaceutical intervention and drug design. The structural and functional characterizations of the NR superfamily represent an important challenge of biomedical research. The crystal structures of the LBDs of less that half of the 48 NRs present in the human genome are known today. Only one LBD of another specie has been structurally characterized.

A structural genomics project has now been launched to fully characterize the LBD structure of all human and insect NRs. For each NR, several crystal structures will be necessary, that of the protein alone and those of the various related complexes (with ligands and cofactors). This project should lead to the discovery of ligands for orphan receptors. One major difficulty of such a program is the protein stability and solubility, as well as its active conformation which is for most NRs, dependent of the presence of a specific ligand. We will present the chosen strategy and the first results.