Advances in Vitamin D Receptor Function and Evolution Based on the 3D Structure of the Lamprey Ligand-Binding Domain br

1 alpha,25-dihydroxyvitamin D3 (1,25D3) regulates many physio-logical processes in vertebrates by binding to the vitamin D receptor (VDR).Phylogenetic analysis indicates that jawlessfishes are the most basalvertebrates exhibiting a VDR gene. To elucidate the mechanism drivingVDR activation during evolution, we determined the crystal structure of the VDR ligand-binding domain (LBD) complex from the basal vertebrate Petromyzon marinus, sea lamprey (lVDR). Comparison of three-dimensionalcrystal structures of the lVDR-1,25D3complex with higher vertebrate VDR-1,25D3structures suggests that 1,25D3binds to lVDR similarly to humanVDR, but with unique features for lVDR around linker regions between H11and H12 and between H9 and H10. These structural differences maycontribute to the marked species differences in transcriptional responses. Furthermore, residue co-evolution analysis of VDR across vertebrates identifies amino acid positions in H9 and the large insertion domain VDR LBD specific as correlated