Session: S13-Evolution of Nuclear Receptors
Room 256 (Moscone Center)
Nuclear receptors are a family of transcription factors that evolved from a ligand-activated receptor in the ancestor of all metazoans. The evolutionary history of these proteins involved duplication and diversification resulting in altered ligand specificity or loss. Here we explore the evolutionary re-acquisition of ligand recognition in a receptor lineage that lost ligand activation. We isolated the ERR of the nemertean worm Paranemertes ERR and found that it lacks constitutive activity and is specifically activated by 3-hydroxy hormones. The X-ray crystal structure of this receptor with estradiol reveals that the ligand is positioned within the pocket in a novel orientation radically different from that of other nuclear receptors. By combining phylogenetics, ancestral protein reconstruction, and functional assays, we identified the molecular substitutions that were responsible for this new function. This work reveals the detailed biochemical mechanisms by which a nuclear receptor evolved ligand activation from a constitutively activate ancestral protein.