Evidence that nuclear receptors evolved from terpene synthases

Ligand-activated nuclear receptors (NRs) including steroid receptors orchestrate development, growth, and reproduction across all animal lifeforms - the Metazoa - but how NRs evolved remains mysterious. Given the universality of terpenoids - including steroids and retinoids - as activating NR ligands, we asked if NRs might have evolved from enzymes that catalyze terpene synthesis and metabolism. We provide evidence suggesting that NRs are a sub-branch of the terpene synthase (TS) enzyme superfamily. Based on over ten thousand 3D structural comparisons, backed up by multiple primary sequence alignments and mapping of ligand-contacting residues, we report that the NR ligand-binding domain and TS enzymes share a conserved core of seven α-helical segments. Primary sequence comparisons reveal potential amino acid sequence similarities between NRs and the subfamily of cis-isoprene transferases, in particular dehydrodolichyl pyrophosphate synthase (DHDPPS) and its obligate partner, NUS1/NOGOB receptor. Our results suggest that a ligand-gated receptor may have arisen from an enzyme antecedent, and thus resolve the long-standing debate about whether the ancestral NR was unliganded. This would also explain aspects of NR ligand 'promiscuity', with implications for the development of pharmaceuticals targeting NRs and TS enzymes.