Structural studies on nuclear receptors

Abstract.

Nuclear receptors are DNA-binding factors which regulate the transcription of sets of specific genes in response to cognate ligands, usually small lipophilic molecules, thus controlling numerous physiological events in development, procreation, homeostasis, and cellular life. Their ligand-dependent activity makes nuclear receptors obvious targets for drug design in many therapeutic areas. Crystallographic studies have revealed the structure of isolated domains but not, yet, of a whole protein, probably due to an intrinsic flexibility at work in nuclear receptor action. The structure of DNA-binding domain dimers in complex with an oligonucleotide has brought insights into how nuclear receptors recognize and bind to their target sequences (‘response elements’). The structure of several ligand-binding domains in different ligation states has provided evidence for a ligand-dependent transcriptional switch and a molecular basis for the mode of action of agonists and antagonists.